FEBS Letters

Inverting character of family GH115 alpha-glucuronidases.

Publication Date: 2010 Aug 28 PMID: 20804758
Authors: Kolenova, K. - Ryabova, O. - Vrsanska, M. - Biely, P.
Journal: FEBS Lett

alpha-Glucuronidases of glycoside hydrolase family 115 of the xylose-fermenting yeast Pichia stipitis and wood-destroying fungus Schizophyllum commune liberate 4-O-methyl-d-glucuronic acid residues from aldouronic acids and glucuronoxylan. The specific activities of both enzymes increased with polymerization degree of the acidic xylooligosaccharides and were inhibited by linear beta-1,4-xylooligosaccharides. These results suggest interaction of the enzyme with several xylopyranosyl residues of the xylan main chain. Using (1)H NMR spectroscopy and reduced aldopentaouronic acid (MeGlcA(3)Xyl(4)-ol) as a substrate, it was found that both enzymes are inverting glycoside hydrolases releasing 4-O-methyl-d-glucuronic acid (MeGlcA) as its beta-anomer.

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Modulation of interferon signaling by hepatitis C virus non-structural 5A protein: Implication of genotypic difference in interferon treatment.

Publication Date: 2010 Aug 28 PMID: 20804757
Authors: Kang, S. M. - Won, S. J. - Lee, G. H. - Lim, Y. S. - Hwang, S. B.
Journal: FEBS Lett

Interferon (IFN) response rate in hepatitis C virus (HCV) patients has been varied with genotypes. In this study, we investigated the effects of HCV NS5A protein on IFN resistance and compared the genotypic differences of NS5A. We showed that IFN-alpha-, poly I:C-, and Sendai virus-induced ISRE transcriptional activities were inhibited by both genotype 1b and 2a NS5A protein. We demonstrated that not only genotype 1b but also genotype 2a NS5A exerted the similar extent of IFN-alpha-induced antiviral activity. We showed that NS5A derived from both genotype 1b and 2a showed no significant differential IFN responses as seen in HCV patients. These data imply that some other host factor may be involved in genotypic differences of IFN antagonism in HCV patients.

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The density of extracellular matrix proteins regulates inflammation and insulin signaling in adipocytes.

Publication Date: 2010 Aug 28 PMID: 20804756
Authors: Li, Q. - Hata, A. - Kosugi, C. - Kataoka, N. - Funaki, M.
Journal: FEBS Lett

Cells can not only sense the type of extracellular matrix (ECM) protein that is present in the microenvironment, but they can also sense its density. Here, we investigated the effects of ECM protein density on adipokine secretion and insulin signaling in adipocytes. To this end, 3T3-L1 adipocytes were cultured on the surface of polyacrylamide gels that were coated with gradient densities of a collagen type I and fibronectin mixture. We found that high density ECM causes a decrease in insulin signaling and adiponectin secretion, whereas the secretion of monocyte chemoattractant protein-1 (MCP-1) was increased via the activation of nuclear factor-kappaB (NF-kappaB). These results indicate that the density of the ECM directly regulates the inflammatory response and insulin sensitivity of adipocytes. STRUCTURED SUMMARY: MINT-7992217: Irs1 (uniprotkb:P35569) physically interacts (MI:0915) with Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha (uniprotkb:P26450) by anti bait coimmunoprecipitation (MI:0006).

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Identification of ptpro as a novel target gene of Wnt signaling and its potential role as a receptor for Wnt.

Publication Date: 2010 Aug 27 PMID: 20804755
Authors: Kim, M. - Kim, H. - Jho, E. H.
Journal: FEBS Lett

Wnt/beta-catenin signaling plays critical roles in embryonic development and tissue homeostasis in adults by controlling the expression of target genes. We found that expression of ptpro, which encodes a receptor protein tyrosine phosphatase type O, was induced by Wnt/beta-catenin signaling in a Tcf/Lef1-dependent manner. Biochemical assays found that PTPRO interacted with Wnt via its extracellular domain. In addition, ectopic expression of this extracellular domain inhibited Wnt-mediated reporter activity. These results suggest that ptpro is a target gene of Wnt/beta-catenin signaling and that PTPRO may function as a novel receptor for Wnt. STRUCTURED SUMMARY: MINT-7992076: Ptpro (uniprotkb:Q7TSY7) physically interacts (MI:0915) with Wnt3a (uniprotkb:P27467) by anti tag coimmunoprecipitation (MI:0007) MINT-7992094: Ptpro (uniprotkb:Q7TSY7) binds (MI:0407) to Wnt-3a (uniprotkb:P27467) by cross-linking study (MI:0030).

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Lysophosphatidic acid stimulates gastric cancer cell proliferation via ERK1-dependent upregulation of sphingosine kinase 1 transcription.

Publication Date: 2010 Aug 27 PMID: 20804754
Authors: Ramachandran, S. - Shida, D. - Nagahashi, M. - Fang, X. - Milstien, S. - Takabe, K. - Spiegel, S.
Journal: FEBS Lett

In MKN1 gastric cancer cells, lysophosphatidic acid (LPA) upregulates expression of sphingosine kinase 1 (SphK1) and its downregulation or inhibition suppresses LPA-mediated proliferation. Although LPA activates numerous signaling pathways downstream of its receptors, including ERK1/2, p38, JNK, and Akt, and the transactivation of the EGF receptor, pharmacological and molecular approaches demonstrated that only activation of ERK1, in addition to the CCAAT/enhancer-binding protein beta (C/EBPbeta) transcription factor, is involved in transcriptional upregulation of SphK1 by LPA. Our data implicate ERK1 as an important mediator of LPA signaling leading to upregulation of SphK1 and point to SphK1 and S1P production as potential therapeutic targets in gastric cancer.

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Activation of human monocytes by a formyl peptide receptor 2-derived pepducin.

Publication Date: 2010 Aug 27 PMID: 20804753
Authors: Lee, H. Y. - Kim, S. D. - Shim, J. W. - Kim, H. J. - Kwon, J. Y. - Kim, J. M. - Baek, S. H. - Park, J. S. - Bae, Y. S.
Journal: FEBS Lett

We synthesized and investigated the effect of formyl peptide receptor 2 (FPR2)-derived pepducins in human monocytes. The FPR2-based cell-penetrating lipopeptide, "pepducin" (F2pal-16), stimulated intracellular calcium increase in human monocytes via pertussis toxin-sensitive G-protein and phospholipase C activity. From a functional aspect, we showed that F2pal-16 stimulated monocyte chemotaxis. F2pal-16 also stimulated the generation of superoxide anion in human monocytes. Moreover, F2pal-16 dramatically increased the production of several kinds of pro-inflammatory cytokines (CXCL8, CCL2, IL-1beta, and TNF-alpha) in human monocytes via NF-kappaB activation. Since FPR2 plays an important role in immune responses, F2pal-16 can serve as a useful reagent for the study of FPR2-mediated immune modulation.

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Knockdown of apoptosis signal-regulating kinase 1 modulates basal glycogen synthase kinase-3beta kinase activity and regulates cell migration.

Publication Date: 2010 Aug 26 PMID: 20800594
Authors: Noh, K. T. - Cho, S. G. - Choi, E. J.
Journal: FEBS Lett

GSK-3beta is a basally active kinase. Axin forms a complex with GSK-3beta and beta-catenin; this complex promotes the GSK-3beta-dependent phosphorylation of beta-catenin, thereby inducing its degradation. However, the inhibition of GSK-3beta provokes cell migration via the dysregulation of beta-catenin. In this study, we determined that the level of apoptosis signal-regulating kinase 1 (ASK1) was lower in a metastatic breast cancer cell line, compared to that of non-metastatic cancer cell lines and the knockdown of ASK1 not only induces beta-catenin activation via the inhibition of GSK-3beta and collapsing the subsequent protein complex by regulating Axin dynamics, but also stimulates cell migration. Together, the blockage of the GSK-3beta-beta-catenin pathway resulting from the knockdown of ASK1 modulates the migration of breast cancer cells.

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A model for signaling specificity of Wnt/Frizzled combinations through co-receptor recruitment.

Publication Date: 2010 Aug 26 PMID: 20800062
Authors: Verkaar, F. - Zaman, G. J.
Journal: FEBS Lett

Wnts control mammalian developmental morphogenesis and are critical for adult stem cell maintenance. Wnts initiate several intracellular signaling cascades, such as Wnt/beta-catenin-, Wnt/Ca(2+)- and Wnt/ROR2-signaling. Signaling preference of Wnts for these various pathways is thought to depend on the repertoire of receptors present on recipient cells. Here, we propose a further refinement of this receptor model and hypothesize that Wnt signaling specificity depends on co-receptor recruitment upon binding of Wnt to Frizzled receptor molecules. In this model, recruitment of LRP5/6 leads to activation of Wnt/beta-catenin signaling, whereas signaling through other pathways is mediated by recruiting ROR2.

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GPR48-Induced keratinocyte proliferation occurs through HB-EGF mediated EGFR transactivation.

Publication Date: 2010 Aug 21 PMID: 20732323
Authors: Wang, Z. - Jin, C. - Li, H. - Li, C. - Hou, Q. - Liu, M. - Dong, X. D. - Tu, L.
Journal: FEBS Lett

GPR48 can mediate keratinocyte proliferation and migration. Our investigations showed that AG1478, an inhibitor of EGFR tyrosine kinase, could block GPR48-mediated cellular processes. AG1478 treatment of Gpr48(+/+) cells also decreased phosphorylation of EGFR, ERK and STAT3. Subsequent screening using conditioned media immunodepleted of EGFR ligands identified HB-EGF as the ligand responsible for phosphorylation of EGFR, ERK and STAT3. HB-EGF was reduced in Gpr48(-/-) cell culture medium, but its addition restored the phosphorylation of EGFR, ERK, STAT3, as well as cell proliferation. Confirmation that GPR48 mediates EGFR signaling pathway through HB-EGF was subsequently performed using an inhibitor of HB-EGF.

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Pseudomonas syringae infection triggers de novo synthesis of phytosphingosine from sphinganine in Arabidopsis thaliana.

Publication Date: 2010 Aug 21 PMID: 20732322
Authors: Peer, M. - Stegmann, M. - Mueller, M. J. - Waller, F.
Journal: FEBS Lett

Sphingolipids are important membrane components and also regulate cell proliferation and apoptosis. We detected a fast increase of the free sphingobase t18:0 (phytosphinganine) in Arabidopsis leaves after inoculation with an avirulent strain of the bacterial pathogen Pseudomonas syringae pathovar tomato, characterized by host cell death reactions. The induction of phytosphinganine was more transient in virulent interactions lacking cell death reactions, suggesting a positive role of t18:0 in the plants' response to pathogens, e.g. the hypersensitive response. In the mutant sphingobase hydroxylase 1 (sbh1-1), Pseudomonas induced elevated free d18:0 levels. As total t18:0 contents (after hydrolysis of ceramides) were not reduced in sbh1-1, the pathogen-triggered t18:0 increase most likely results from de novo synthesis from d18:0 which would require SBH1.

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Induction of growth arrest by miR-542-3p that targets survivin.

Publication Date: 2010 Aug 20 PMID: 20728447
Authors: Yoon, S. - Choi, Y. C. - Lee, S. - Jeong, Y. - Yoon, J. - Baek, K.
Journal: FEBS Lett

Survivin is a protein which functions as a mitotic regulator as well as apoptosis inhibitor. In this study, we show that introduction of synthetic miR-542-3p mimetic reduced both mRNA and protein levels of survivin. In A549 cells, luciferase reporter assay revealed that miR-542-3p targeted predicted binding sites in the 3'-untranslated region (3'-UTR) of survivin. We also demonstrate that ectopic expression of miR-542-3p inhibited cell proliferation by inducing Gap 1 (G1) and Gap 2/Mitosis (G2/M) cell cycle arrest. Collectively, these results suggest that survivin is a direct target of miR-542-3p and growth inhibition by miR-542-3p may have a potential utility as an anti-cancer therapy.

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The FEBS Letters SDA corpus: A collection of protein interaction articles with high quality annotations for the BioCreative II.5 online challenge and the text mining community.

Publication Date: 2010 Aug 20 PMID: 20728446
Authors: Leitner, F. - Krallinger, M. - Cesareni, G. - Valencia, A.
Journal: FEBS Lett

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A novel Aspergillus oryzae esterase that hydrolyzes 4-hydroxybenzoic acid esters.

Publication Date: 2010 Aug 20 PMID: 20728445
Authors: Koseki, T. - Mihara, K. - Murayama, T. - Shiono, Y.
Journal: FEBS Lett

In this study we report the biochemical characterization of a hypothetical protein from Aspergillus oryzae exhibiting sequence identity with feruloyl esterase and tannase from the genus Aspergillus. The purified recombinant protein showed a hydrolytic activity toward the ethyl, propyl, or butyl esters of 4-hydroxybenzoic acid, but did not show feruloyl esterase or tannase activity. Finally, the enzyme decreased the antimicrobial activity of parabens against A. oryzae via hydrolysis of the ester bond present in butyl 4-hydroxybenzoic acid.

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Receptors and signaling mechanisms for B-lymphocyte activation, proliferation and differentiation - Insights from both in vivo and in vitro approaches.

Publication Date: 2010 Aug 20 PMID: 20728444
Authors: Maddaly, R. - Pai, G. - Balaji, S. - Sivaramakrishnan, P. - Srinivasan, L. - Sunder, S. S. - Paul, S. F.
Journal: FEBS Lett

During the last three decades, a number of B-lymphocyte specific surface antigens have been defined some of which may also show activation/differentiation specific expression. Here, we review the various signaling events and the receptor-ligand interactions for B-cell development, activation and differentiation. Our discussion and presentation include reviewing the in vivo and in vitro mechanisms. Focus is on the experiments that give us valuable insights into the B cell signaling mechanisms in vitro. Three significant pathways in B-cell development - c-Kit, FLT-3 and IL-7 signaling pathways are elucidated upon. Both antigen dependent and antigen independent mechanisms of B cell stimulation are also reviewed.

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Alternative splicing of genes during neuronal differentiation of NT2 pluripotential human embryonal carcinoma cells.

Publication Date: 2010 Aug 20 PMID: 20728443
Authors: Wakamatsu, A. - Imai, J. I. - Watanabe, S. - Isogai, T.
Journal: FEBS Lett

We analyzed the mRNA diversity of genes after inducing neuronal differentiation in human NT2 teratocarcinoma cells using all-trans retinoic acid (RA). DNA microarray analyses of cells treated with RA identified 358 RA-responsive genes. mRNA diversity analysis revealed that 274 genes produced multiple protein-coding transcripts by alternative splicing. Among these 274 genes, we chose 26 genes that showed AS in their C-terminus and 12 transcription factor genes for further analysis. By using transcript-specific primers, we performed quantitative real-time PCR analysis to examine the expression profiles of all the protein-coding transcripts. Consequently, we identified genes which showed different RA-induced changes in the expression of their protein-coding transcripts.

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Building arks for tRNA: Structure and function of the Arc1p family of non-catalytic tRNA-binding proteins.

Publication Date: 2010 Aug 20 PMID: 20728442
Authors: Karanasios, E. - Simos, G.
Journal: FEBS Lett

Following the intricate architecture of the eukaryotic cell, protein synthesis involves formation of many macromolecular assemblies, some of which are composed by tRNA-aminoacylation enzymes. Protein-protein and protein-tRNA interactions in these complexes can be facilitated by non-catalytic tRNA-binding proteins. This review focuses on the dissection of the molecular, structural and functional properties of a particular family of such proteins: yeast Arc1p and its homologues in prokaryotes and higher eukaryotes. They represent paradigms of the strategies employed for the organization of sophisticated and dynamic nanostructures supporting spatio-temporal cellular organization.

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Epitope tag-induced synthetic lethality between cohesin subunits and Ctf7/Eco1 acetyltransferase.

Publication Date: 2010 Aug 20 PMID: 20728441
Authors: Maradeo, M. E. - Skibbens, R. V.
Journal: FEBS Lett

Ctf7/Eco1-dependent acetylation of Smc3 is essential for sister chromatid cohesion. Here, we use epitope tag-induced lethality in cells diminished for Ctf7/Eco1 activity to map cohesin architecture in vivo. Tagging either Smc1 or Mcd1/Scc1, but not Scc3/Irr1, appears to abolish access to Smc3 in ctf7/eco1 mutant cells, suggesting that Smc1 and Smc3 head domains are in direct contact with each other and also with Mcd1/Scc1. Thus, cohesin complexes may be much more compact than commonly portrayed. We further demonstrate that mutation in ELG1 or RFC5 anti-establishment genes suppress tag-induced lethality, consistent with the notion that the replication fork regulates Ctf7/Eco1.

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ATR-FTIR study of the protonation states of the Glu residue in the multicopper oxidases, CueO and bilirubin oxidase.

Publication Date: 2010 Aug 18 PMID: 20727354
Authors: Iwaki, M. - Kataoka, K. - Kajino, T. - Sugiyama, R. - Morishita, H. - Sakurai, T.
Journal: FEBS Lett

Redox-induced protonation state changes of the Glu residue in the multicopper oxidases, CueO and bilirubin oxidase (BO), were studied by attenuated total reflectance-Fourier transform infrared spectroscopy. By monitoring IR bands of the carboxylic acid CO stretch in the wild-type and Glu-to-Gln mutant enzymes the Glu506 of CueO (Glu463 of BO) was found to be unprotonated in the oxidised and protonated in the reduced forms. The results provided direct evidence for proton uptake by the Glu, suggesting it plays a key role in the proton donation to the activated oxygen species in the catalytic cycle.

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DNA methylation systems and targets in plants.

Publication Date: 2010 Aug 18 PMID: 20727353
Authors: Meyer, P.
Journal: FEBS Lett

Plants contain three distinct DNA methyltransferase types that are responsible for the establishment and maintenance of cytosine methylation patterns at heterochromatic and euchromatic target regions. RNA transcripts play an important role in recruiting DNA methylation systems to specific loci, where methylation patterns are controlled by distinct epigenetic pathways that often work co-operatively and in competition with demethylation functions. DNA methylation patterns are faithfully propagated by maintenance systems that involve re-enforcing feedback effects between DNA methylation and histone marks. Our detailed knowledge about the composition of DNA methylation patterns is contrasted by a poorer understanding of the variability of DNA methylation and its contribution to gene regulation, genome evolution and adaptation to environmental changes.

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NADH oxidase activity of Bacillus subtilis nitroreductase NfrA1: Insight into its biological role.

Publication Date: 2010 Aug 18 PMID: 20727352
Authors: Cortial, S. - Chaignon, P. - Iorga, B. I. - Aymerich, S. - Truan, G. - Gueguen-Chaignon, V. - Meyer, P. - Morera, S. - Ouazzani, J.
Journal: FEBS Lett

NfrA1 nitroreductase from the Gram-positive bacterium Bacillus subtilis is a member of the NAD(P)H/FMN oxidoreductase family. Here, we investigated the reactivity, the structure and kinetics of NfrA1, which could provide insight into the unclear biological role of this enzyme. We could show that NfrA1 possesses an NADH oxidase activity that leads to high concentrations of oxygen peroxide and an NAD(+) degrading activity leading to free nicotinamide. Finally, we showed that NfrA1 is able to rapidly scavenge H(2)O(2) produced during the oxidative process or added exogenously. STRUCTURED SUMMARY: MINT-7990140: nfrA1 (uniprotkb:P39605) and nfrA1 (uniprotkb:P39605) bind (MI:0407) by X-ray crystallography (MI:0114).

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ARF-dependent regulation of ATM and p53 associated KZNF (Apak) protein activity in response to oncogenic stress.

Publication Date: 2010 Aug 14 PMID: 20713054
Authors: Wang, S. - Tian, C. - Xing, G. - Gao, M. - Jiao, W. - Xiao, T. - Yin, Y. - He, F. - Zhang, L.
Journal: FEBS Lett

The KRAB-type zinc-finger protein Apak (ATM and p53 associated KZNF protein) specifically suppresses p53-mediated apoptosis. Upon DNA damage, Apak is phosphorylated and inhibited by ATM kinase, resulting in p53 activation. However, how Apak is regulated in response to oncogenic stress remains unknown. Here we show that upon oncogene activation, Apak is inhibited in the tumor suppressor ARF-dependent but ATM-independent manner. Oncogene-induced ARF protein directly interacts with Apak and competes with p53 to bind to Apak, resulting in Apak dissociation from p53. Thus, Apak is differentially regulated in the ARF and ATM-dependent manner in response to oncogenic stress and DNA damage, respectively. STRUCTURED SUMMARY: MINT-7989670: p53 (uniprotkb:P04637) binds (MI:0407) to APAK (uniprotkb:Q8TAQ5) by pull down (MI:0096)MINT-7989812: HDM2 (uniprotkb:Q00987) physically interacts (MI:0915) with ARF (uniprotkb:Q8N726-1) by anti bait coimmunoprecipitation (MI:0006)MINT-7989603, MINT-7989626: APAK (uniprotkb:Q8TAQ5) physically interacts (MI:0915) with ARF (uniprotkb:Q8N726-1) by anti bait coimmunoprecipitation (MI:0006)MINT-7989653: ARF (uniprotkb:Q8N726-1) binds (MI:0407) to APAK (uniprotkb:Q8TAQ5) by pull down (MI:0096)MINT-7989686, MINT-7989705, MINT-7989747:APAK (uniprotkb:Q8TAQ5) physically interacts (MI:0915) with ARF (uniprotkb:Q8N726-1) by anti tag coimmunoprecipitation (MI:0007)MINT-7989724: APAK (uniprotkb:Q8TAQ5) physically interacts (MI:0914) with ARF (uniprotkb:Q8N726-1) and p53 (uniprotkb:P04637) by anti tag coimmunoprecipitation (MI:0007)MINT-7989635: ARF (uniprotkb:Q8N726-1) and APAK (uniprotkb:Q8TAQ5) colocalize (MI:0403) by fluorescence microscopy (MI:0416)MINT-7989584, MINT-7989773: APAK (uniprotkb:Q8TAQ5) physically interacts (MI:0915) with p53 (uniprotkb:P04637) by anti tag coimmunoprecipitation (MI:0007).

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Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2.

Publication Date: 2010 Aug 13 PMID: 20709061
Authors: Umehara, T. - Nakamura, Y. - Wakamori, M. - Ozato, K. - Yokoyama, S. - Padmanabhan, B.
Journal: FEBS Lett

The BET family proteins recognize acetylated chromatin through their two bromodomains, acting as transcriptional activators or tethering viral genomes to the mitotic chromosomes of their host. The structural mechanism for how the N-terminal bromodomain of human BRD2 (BRD2-BD1) deciphers the mono-acetylated status of histone H4 tail was recently reported. Here we show the crystal structure of the second bromodomain of BRD2 (BRD2-BD2) in complex with the di-acetylated histone H4 tail (H4K5ac/K12ac). To our surprise, a single K5ac/K12ac peptide interacts with two BRD2-BD2 molecules simultaneously: the K5ac residue binds to one BRD2-BD2 molecule while the K12ac residue binds to another. These results provide a structural basis for the recognition of two different patterns of the histone acetylation status by a single bromodomain. STRUCTURED SUMMARY: MINT-7989882, MINT-7989824, MINT-7989846, MINT-7989865: H4 (uniprotkb:P62805) binds (MI:0407) to BRD2 (uniprotkb:P25440) by surface plasmon resonance (MI:0107) MINT-7989539: H4 (uniprotkb:P62805) and BRD2 (uniprotkb:P25440) bind (MI:0407) by X-ray crystallography (MI:0114).

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The JNK inhibitor SP600125 enhances dihydroartemisinin-induced apoptosis by accelerating Bax translocation into mitochondria in human lung adenocarcinoma cells.

Publication Date: 2010 Aug 13 PMID: 20709060
Authors: Lu, Y. Y. - Chen, T. S. - Wang, X. P. - Qu, J. L. - Chen, M.
Journal: FEBS Lett

The C-Jun N-terminal Kinase (JNK) inhibitor SP600125 is widely used to inhibit the JNK-mediated Bax activation and cell apoptosis. However, this report demonstrates that SP600125 synergistically enhances the dihydroartemisinin (DHA)-induced human lung adenocarcinoma cell apoptosis by accelerating Bax translocation and subsequent intrinsic apoptotic pathway involving mitochondrial membrane depolarization, cytochrome c release, caspase-9 and caspase-3 activation. The dynamical analysis of GFP-Bax mobility inside single living cells using fluorescence recovery after photobleaching revealed that SP600125 aggravated the DHA-induced decrease of Bax mobility and Bax translocation. These results for the first time present a novel pro-apoptotic action of SP600125 in DHA-induced apoptosis.

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The double mutation DeltaL6MW241F in PsbO, the photosystem II manganese stabilizing protein, yields insights into the evolution of its structure and function.

Publication Date: 2010 Aug 12 PMID: 20708615
Authors: Popelkova, H. - Commet, A. - Yocum, C. F.
Journal: FEBS Lett

The W241F mutation in spinach manganese-stabilizing protein (PsbO) decreases binding to photosystem II (PSII); its thermostability is increased and reconstituted activity is lower [Wyman et al. (2008) Biochemistry 47, 6490-6498]. The results reported here show that W241F cannot adopt a normal solution structure and fails to reconstitute efficient Cl(-) retention by PSII. An N-terminal truncation of W241F, producing the DeltaL6MW241F double mutant that resembles some features of cyanobacterial PsbO, significantly repairs the defects in W241F. Our data suggest that the C-terminal F-->W mutation likely evolved in higher plants and green algae in order to preserve proper PsbO folding and PSII binding and assembly, which promotes efficient Cl(-) retention in the oxygen-evolving complex.

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Insights into the genomic features and evolutionary impact of the genes configuring duplicated pseudogenes in human.

Publication Date: 2010 Aug 12 PMID: 20708614
Authors: Sen, K. - Podder, S. - Ghosh, T. C.
Journal: FEBS Lett

Pseudogenes, regarded as 'genomic fossils', are DNA sequences resembling functional genes in perspective of sequence homology but completely non-functional. In this study, we explored the unique characteristic features of human genes, configuring classical duplicated pseudogenes. We found that progenitors of duplicated pseudogenes are characterized by a high expressivity, and ability to encode hub-proteins in association with a high evolutionary rate. Such unusual features are endorsed by longer protein length, elevated CpG content, and a high recombination rate. The non-functionalization of their duplicated copies can be attributed to the overabundance of gene paralog number in concert with functional redundancy.

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Current inhibition of human EAG1 potassium channels by the Ca(2+) binding protein S100B.

Publication Date: 2010 Aug 12 PMID: 20708613
Authors: Sahoo, N. - Troger, J. - Heinemann, S. H. - Schonherr, R.
Journal: FEBS Lett

Voltage-dependent human ether a go-go (hEAG1) potassium channels are implicated in neuronal signaling as well as in cancer cell proliferation. Unique sensitivity of the channel to intracellular Ca(2+) is mediated by calmodulin (CaM) binding to the intracellular N- and C-termini of the channel. Here we show that application of the acidic calcium-binding protein S100B to inside-out patches of Xenopus oocytes causes Ca(2+)-dependent inhibition of expressed hEAG1 channels. Protein pull-down assays and fluorescence correlation spectroscopy (FCS) revealed that S100B binds to hEAG1 and shares the same binding sites with CaM. Thus, S100B is a potential alternative calcium sensor for hEAG1 potassium channels. STRUCTURED SUMMARY: MINT-7988123: CaM (uniprotkb:P62158) and EAG1 alpha (uniprotkb:O95259) physically interact (MI:0915) by competition binding (MI:0405)MINT-7988019, MINT-7988052: EAG1 alpha (uniprotkb:O95259) binds (MI:0407) to s100B (uniprotkb:P02638) by pull down (MI:0096)MINT-7988074: EAG1 alpha (uniprotkb:O95259) and s100B (uniprotkb:P02638) physically interact (MI:0915) by competition binding (MI:0405)MINT-7988100:CaM (uniprotkb:P62158) and EAG1 alpha (uniprotkb:O95259) bind (MI:0407) by fluorescence correlation spectroscopy (MI:0052).

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DJ-1, an oncogene and causative gene for familial Parkinson's disease, is essential for SV40 transformation in mouse fibroblasts through up-regulation of c-Myc.

Publication Date: 2010 Aug 12 PMID: 20708612
Authors: Kim, Y. C. - Kitaura, H. - Iguchi-Ariga, S. M. - Ariga, H.
Journal: FEBS Lett

Simian virus 40 (SV40) is a tumor virus and its early gene product large T-antigen (LT) is responsible for the transforming activity of SV40. Parkinson's disease causative gene DJ-1 is also a ras-dependent oncogene, but the mechanism of its oncogene function is still not known. In this study, we found that there were no transformed foci when fibroblasts from DJ-1-knockout mice were transfected with LT. We also found that DJ-1 directly bound to LT and that the expression level of c-Myc in transformed cells was parallel to that of DJ-1. These findings indicate that DJ-1 is essential for SV40 transformation. STRUCTURED SUMMARY: MINT-7988969: DJ-1 (uniprotkb:Q99497) binds (MI:0407) to LT SV40 (uniprotkb:P03070) by pull down (MI:0096) MINT-7988948: LT SV40 (uniprotkb:P03070) physically interacts (MI:0914) with DJ-1 (uniprotkb:Q99LX0) and p53 (uniprotkb:P02340) by anti bait coimmunoprecipitation (MI:0006).

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Dysregulation of microRNAs in cancer: Playing with fire.

Publication Date: 2010 Aug 11 PMID: 20708002
Authors: Melo, S. A. - Esteller, M.
Journal: FEBS Lett

MicroRNAs [1] have emerged as key post-transcriptional regulators of gene expression, involved in various physiological and pathological processes. It was found that several miRNAs are directly involved in human cancers, including lung, breast, brain, liver, colon cancer and leukemia. In addition, some miRNAs may function as oncogenes or tumor suppressors in tumor development. Furthermore, a widespread down-regulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis [2-5]. More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites, frequently amplified or deleted in human cancer, suggesting an important role in malignant transformation. A better understanding of the miRNA regulation and misexpression in cancer may ultimately yield further insight into the molecular mechanisms of tumorigenesis and new therapeutic strategies may arise against cancer. Here, we discuss the occurrence of the deregulated expression of miRNAs in human cancers and their importance in the tumorigenic process.

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A cytotoxic peptide from a marine sponge exhibits ion channel activity through vectorial-insertion into the membrane.

Publication Date: 2010 Aug 11 PMID: 20699099
Authors: Iwamoto, M. - Shimizu, H. - Muramatsu, I. - Oiki, S.
Journal: FEBS Lett

A cytotoxic peptide, polytheonamide B (pTB), from marine sponge was examined for cytotoxic spectrum and specific activity to mammalian cells was demonstrated. pTB is composed of alternative D- and L-amino acid residues throughout the 48-mer peptide. This suggests the formation of a beta-helix similar to gramicidin channels. Planar bilayer experiments revealed that pTB forms monovalent cation-selective channels, being compatible with the inner pore diameter of approximately 4A for a beta-helical structure. pTB penetrated vectorially into the membrane, formed a channel by means of a single molecule, and remained in the membrane. These functional properties may account for specific cytotoxic activity.

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Reporter gene expression at single-cell level characterized with real-time RT-PCR, chemiluminescence, fluorescence, and electrochemical imaging.

Publication Date: 2010 Aug 11 PMID: 20699098
Authors: Shiku, H. - Okazaki, D. - Suzuki, J. - Takahashi, Y. - Murata, T. - Akita, H. - Harashima, H. - Ino, K. - Matsue, T.
Journal: FEBS Lett

mRNA from single cells was quantified using real-time RT-PCR after recording the address and reporter protein activity with chemiluminescence, fluorescence, and electrochemical techniques, using luciferase, green fluorescent protein, and secreted alkaline phosphatase. mRNA copy number ranging from below 10(3) to 10(7) in single cells showed a lognormal distribution for both externally introduced reporter genes and internally expressed genes. The fluctuation in the gene expression decreased with the increase of the number of cells picked but did not decrease with the increase of mRNA copy number per cell. We found that the correlation coefficients for mRNA and protein expression in logarithmic plot at single-cell level were much lower than 1.00.

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Structural identity of telomeric complexes.

Publication Date: 2010 Sep 10 PMID: 20696167
Authors: Giraud-Panis, M. J. - Pisano, S. - Poulet, A. - Le Du, M. H. - Gilson, E.
Journal: FEBS Lett

A major issue in telomere research is to understand how the integrity of chromosome ends is controlled. Although several nucleoprotein complexes have been described at the telomeres of different organisms, it is still unclear how they confer a structural identity to chromosome ends in order to mask them from DNA repair and to ensure their proper replication. In this review, we describe how telomeric nucleoprotein complexes are structured, comparing different organisms and trying to link these structures to telomere biology. It emerges that telomeres are formed by a complex and specific network of interactions between DNA, RNA and proteins. The fact that these interactions and associated activities are reinforcing each other might help to guaranty the robustness of telomeric functions across the cell cycle and in the event of cellular perturbations. We propose that telomeric nucleoprotein complexes orient cell fate through dynamic transitions in their structures and their organization.

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Mast cell signaling: The role of protein tyrosine kinase Syk, its activation and screening methods for new pathway participants.

Publication Date: 2010 Aug 7 PMID: 20696166
Authors: Siraganian, R. P. - de Castro, R. O. - Barbu, E. A. - Zhang, J.
Journal: FEBS Lett

The aggregation by antigen of the IgE bound to its high affinity receptor on mast cells initiates a complex series of biochemical events that result in the release of inflammatory mediators. The essential role of the protein tyrosine kinase Syk has been appreciated for some time, and newer results have defined the mechanism of its activation. The use of siRNA has defined the relative contribution of Syk, Fyn and Gab2 to signaling and has made possible a screening study to identify previously unrecognized molecules that are involved in these pathways.

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Tankyrase-1 assembly to large protein complexes blocks its telomeric function.

Publication Date: 2010 Aug 7 PMID: 20696165
Authors: Hatsugai, K. - Ohishi, T. - Sugimoto, Y. - Seimiya, H.
Journal: FEBS Lett

Tankyrase-1 poly(ADP-ribosyl)ates the telomere-binding protein TRF1. This post-translational modification dissociates TRF1 from telomeres, enhancing telomerase-mediated telomere elongation. Tankyrase-1 multimerizes via its sterile alpha motif domain, but its functional implication remains elusive. Here, we found that excessive amounts of tankyrase-1 form punctate nuclear foci. This focus formation depends on both homophilic multimerization and heterophilic protein-protein interaction. These foci are functionally dormant because they do not efficiently release TRF1 from telomeres. Consistently, hyper-overexpression of tankyrase-1 attenuates its ability to elongate telomeres. These observations suggest that tankyrase-1 assembly to large protein complexes masks its telomeric function. STRUCTURED SUMMARY: MINT-7987689, MINT-7987677: Tankyrase-1 (uniprotkb:O95271) and TRF1 (uniprotkb:P54274) colocalize (MI:0403) by fluorescence microscopy (MI:0416) MINT-7987977: Tankyrase-1 (uniprotkb:O95271) physically interacts (MI:0915) with TRF1 (uniprotkb:P54274) by anti tag coimmunoprecipitation (MI:0007) MINT-7987998: Tankyrase-1 (uniprotkb:O95271) physically interacts (MI:0915) with Tankyrase-1 (uniprotkb:O95271) by anti tag coimmunoprecipitation (MI:0007).

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POSH2 is a RING finger E3 ligase with Rac1 binding activity through a partial CRIB domain.

Publication Date: 2010 Aug 8 PMID: 20696164
Authors: Karkkainen, S. - van der Linden, M. - Renkema, G. H.
Journal: FEBS Lett

The Plenty of SH3 domains protein (POSH) is an E3 ligase and a scaffold in the JNK mediated apoptosis, linking Rac1 to downstream components. We here describe POSH2 which was identified from a p21-activated kinase 2 (PAK2) interactor screen. POSH2 is highly homologous with other members of the POSH family; it contains four Src homology 3 (SH3) domains and a RING finger domain which confers E3 ligase activity to the protein. In addition POSH2 contains an N-terminal extension which is conserved among its mammalian counterparts. POSH2 interacts with GTP-loaded Rac1. We have mapped this interaction to a previously unrecognized partial Cdc42/Rac1-interactive binding domain. STRUCTURED SUMMARY: MINT-7987761: POSH1 (uniprotkb:Q9HAM2) physically interacts (MI:0915) with Ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007) MINT-7987932: PAK2 (uniprotkb:Q13177) binds (MI:0407) to CDC42 (uniprotkb:Q07912) by solid phase assay (MI:0892) MINT-7987908: POSH1 (uniprotkb:Q9HAM2) binds (MI:0407) to Rac1 (uniprotkb:P63000) by solid phase assay (MI:0892) MINT-7987880: POSH2 (uniprotkb:Q8TEJ3) binds (MI:0407) to Rac1 (uniprotkb:P63000) by solid phase assay (MI:0892) MINT-7987734: POSH2 (uniprotkb:Q8TEJ3) physically interacts (MI:0915) with Ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007) MINT-7987779, MINT-7987804, MINT-7987824, MINT-7987838, MINT-7987853: Rac1 (uniprotkb:P63000) physically interacts (MI:0915) with POSH2 (uniprotkb:Q8TEJ3) by anti tag coimmunoprecipitation (MI:0007) MINT-7987920: PAK2 (uniprotkb:Q13177) binds (MI:0407) to Rac1 (uniprotkb:P63000) by solid phase assay (MI:0892).

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Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654.

Publication Date: 2010 Aug 7 PMID: 20692258
Authors: Dittmann, K. - Mayer, C. - Fehrenbacher, B. - Schaller, M. - Kehlbach, R. - Rodemann, H. P.
Journal: FEBS Lett

Nuclear localisation of EGFR is associated with treatment resistance of tumor cells. The aim of this study was to identify molecular targets to block nuclear shuttling of EGFR. Mutation of Thr654, located within the putative EGFR NLS demonstrated that phosphorylation of this residue is essential for nuclear EGFR shuttling following irradiation. Deletion of Thr654 blocked nuclear transport of EGFR, whereas mutation to Glu increased shuttling. Treatment with a peptide, corresponding to the phosphorylated NLS, abolished nuclear EGFR transport and reduced radiation-induced activation of DNA-PK, essential for DNA-repair. In accordance with that, lack of nuclear EGFR increased residual DNA damage in tumor cells and reduced cellular survival following irradiation. Blockage of nuclear EGFR shuttling may be a new strategy to fight treatment resistance. STRUCTURED SUMMARY: MINT-7987956: Karyopherin alpha (uniprotkb:P52294) physically interacts (MI:0915) with EGFR (uniprotkb:P00533) by anti bait coimmunoprecipitation (MI:0006).

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The correlation coefficient of GC content of the genome-wide genes is positively correlated with animal evolutionary relationships.

Publication Date: 2010 Aug 6 PMID: 20691688
Authors: Du, H. - Hu, H. - Meng, Y. - Zheng, W. - Ling, F. - Wang, J. - Zhang, X. - Nie, Q. - Wang, X.
Journal: FEBS Lett

In this study, we present a new method for evaluating animal evolutionary relationships. We used the GC% levels of genome-wide genes to determine the correlation between the GC% content and evolutionary relationship. The correlation coefficients of the GC% content of the orthologous genes of the paired animal species were calculated for a total of 21 species, and the evolutionary branching dates of these 21 species were derived from fossil records. The correlation coefficient of the GC% content of the orthologous genes of the species pair under study served as an indicator of their evolutionary relationship. Moreover, there was a decreasing linear relationship between the correlation coefficient and evolutionary branching date (R(2)=0.930).

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Cyclic cytidine 3',5'-monophosphate (cCMP) signals via cGMP kinase I.

Publication Date: 2010 Aug 6 PMID: 20691687
Authors: Desch, M. - Schinner, E. - Kees, F. - Hofmann, F. - Seifert, R. - Schlossmann, J.
Journal: FEBS Lett

We analysed the function and intracellular signalling of the cyclic pyrimidinic nucleotide cCMP. The membrane-permeable cCMP analogue dibutyryl-cCMP mediated mouse aorta relaxation. cCMP activated purified cGMP-dependent protein kinase (cGK) Ialpha and Ibeta and stimulated cGK in aorta lysates. cCMP-induced relaxation was abolished in cGKI-knockout tissue. Additionally, deletion of inositol-trisphosphate receptor associated cGKI substrate (IRAG) suppressed cCMP-mediated relaxation. Signalling of cCMP via cGKI/IRAG appears to be of broader physiological importance because cCMP-mediated inhibition of platelet aggregation was absent in cGKI- and IRAG-deficient platelets. These results demonstrate that cCMP acts as intracellular messenger molecule, most unexpectedly utilizing the cGMP signal transduction pathway.

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Extracellular signal-regulated kinase (ERK) participates in the hypercapnia-induced Na,K-ATPase downregulation.

Publication Date: 2010 Aug 6 PMID: 20691686
Authors: Welch, L. C. - Lecuona, E. - Briva, A. - Trejo, H. E. - Dada, L. A. - Sznajder, J. I.
Journal: FEBS Lett

Hypercapnia has been shown to impair alveolar fluid reabsorption (AFR) by decreasing Na,K-ATPase activity. Extracellular signal-regulated kinase pathway (ERK) is activated under conditions of cellular stress and has been known to regulate the Na,K-ATPase. Here, we show that hypercapnia leads to ERK activation in a time-dependent manner in alveolar epithelial cells (AEC). Inhibition of ERK by U0126 or siRNA prevented both the hypercapnia-induced Na,K-ATPase endocytosis and impairment of AFR. Moreover, ERK inhibition prevented AMPK activation, a known modulator of hypercapnia-induced Na,K-ATPase endocytosis. Accordingly, these data suggest that hypercapnia-induced Na,K-ATPase endocytosis is dependent on ERK activation in AEC and that ERK plays an important role in hypercapnia-induced impairment of AFR in rat lungs.

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Molecular characterization of beta1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS).

Publication Date: 2010 Aug 6 PMID: 20691685
Authors: Bui, C. - Talhaoui, I. - Chabel, M. - Mulliert, G. - Coughtrie, M. W. - Ouzzine, M. - Fournel-Gigleux, S.
Journal: FEBS Lett

beta1,4-Galactosyltransferase 7 (beta4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized beta4GalT7 mutants linked to the progeroid form of Ehlers-Danlos syndrome (EDS), a severe connective tissue disorder. Our results revealed that loss of activity upon L206P substitution due to altered protein folding is the primary cause for the GAG synthesis defect in patients carrying the compound A186D and L206P mutations. We showed that R270C substitution strongly reduced beta4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for beta4GalT7 defects associated with altered GAG synthesis in EDS.

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Isolation of a point-mutated p47 lacking binding affinity to p97ATPase.

Publication Date: 2010 Aug 6 PMID: 20691684
Authors: Kaneko, Y. - Tamura, K. - Totsukawa, G. - Kondo, H.
Journal: FEBS Lett

p47, a p97-binding protein, functions in Golgi membrane fusion together with p97 and VCIP135, another p97-binding protein. We have succeeded in creating p47 with a point mutation, F253S, which lacks p97-binding affinity. p47 mapping experiments revealed that p47 had two p97-binding regions and the F253S mutation occurred in the first p97-binding site. p47(F253S) could not form a complex with p97 and did not caused any cisternal regrowth in an in vitro Golgi reassembly assay. In addition, mutation corresponding to the p47 F253S mutation in p37 and ufd1 also abolished their binding ability to p97. STRUCTURED SUMMARY: MINT-7987189, MINT-7987207, MINT-7987303: p47 (uniprotkb:O35987) binds (MI:0407) to p97 (uniprotkb:Q01853) by pull down (MI:0096) MINT-7987226: p97 (uniprotkb:P46462) binds (MI:0407) to p47 (uniprotkb:O35987) by pull down (MI:0096) MINT-7987348: p97 (uniprotkb:P46462) physically interacts (MI:0915) with Ufd1 (uniprotkb:P70362) by pull down (MI:0096) MINT-7987264: p97 (uniprotkb:P46462) and p47 (uniprotkb:O35987) bind (MI:0407) by competition binding (MI:0405) MINT-7987326: p97 (uniprotkb:P46462) binds (MI:0407) to p37 (uniprotkb:Q0KL01) by pull down (MI:0096).

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Collaboration and competition between DNA double-strand break repair pathways.

Publication Date: 2010 Sep 10 PMID: 20691183
Authors: Kass, E. M. - Jasin, M.
Journal: FEBS Lett

DNA double-strand breaks resulting from normal cellular processes including replication and exogenous sources such as ionizing radiation pose a serious risk to genome stability, and cells have evolved different mechanisms for their efficient repair. The two major pathways involved in the repair of double-strand breaks in eukaryotic cells are non-homologous end joining and homologous recombination. Numerous factors affect the decision to repair a double-strand break via these pathways, and accumulating evidence suggests these major repair pathways both cooperate and compete with each other at double-strand break sites to facilitate efficient repair and promote genomic integrity.

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Fission yeast telomeres forecast the end of the crisis.

Publication Date: 2010 Sep 10 PMID: 20682311
Authors: Dehe, P. M. - Cooper, J. P.
Journal: FEBS Lett

Recent years have placed fission yeast at the forefront of telomere research, as this organism combines a high level of conservation with human telomeres and precise genetic manipulability. Here we highlight some of the latest knowledge of fission yeast telomere maintenance and dysfunction, and illustrate how principles arising from fission yeast research are raising novel questions about telomere plasticity and function in all eukaryotes.

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Crystal structure of Bifidobacterium Longum phosphoketolase; key enzyme for glucose metabolism in Bifidobacterium.

Publication Date: 2010 Aug 3 PMID: 20674574
Authors: Takahashi, K. - Tagami, U. - Shimba, N. - Kashiwagi, T. - Ishikawa, K. - Suzuki, E. I.
Journal: FEBS Lett

The crystal structure of Bifidobacterium longum phosphoketolase, a thiamine diphosphate (TPP) dependent enzyme, has been determined at 2.2A resolution. The enzyme is a dimer with the active sites located at the interface between the two identical subunits with molecular mass of 92.5kDa. The bound TPP is almost completely shielded from solvent except for the catalytically important C2-carbon of the thiazolium ring, which can be accessed by a substrate sugar through a narrow funnel-shaped channel. In silico docking studies of B. longum phosphoketolase with its substrate enable us to propose a model for substrate binding. STRUCTURED SUMMARY: MINT-7985878: PKT (uniprotkb:Q6R2Q7) and PKT (uniprotkb:Q6R2Q7) bind (MI:0407) by X-ray crystallography (MI:0114).

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The role of telomeres and telomerase in stem cell aging.

Publication Date: 2010 Sep 10 PMID: 20674573
Authors: Flores, I. - Blasco, M. A.
Journal: FEBS Lett

Stem cells regenerate our bodies. In a similar manner to match ignition, stem cell "ignition" has to be precisely tuned to avoid uncontrolled proliferation as may occur in tumors or, inversely, the lack of proliferation as happens in degenerative disorders. During the last years it has become evident that telomeres and telomerase are main components of the stem cell "ignition" mechanism, providing a way to restrain cancer and delay aging.

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Knock-out of metacaspase and/or cytochrome c results in the activation of a ROS-independent acetic acid-induced programmed cell death pathway in yeast.

Publication Date: 2010 Aug 20 PMID: 20674572
Authors: Guaragnella, N. - Passarella, S. - Marra, E. - Giannattasio, S.
Journal: FEBS Lett

To gain further insight into yeast acetic acid-induced programmed cell death (AA-PCD) we analyzed the effects of the antioxidant N-acetyl-L-cysteine (NAC) on cell viability, hydrogen peroxide (H(2)O(2)) production, DNA fragmentation, cytochrome c (cyt c) release and caspase-like activation in wild type (wt) and metacaspase and/or cyt c-lacking cells. We found that NAC prevents AA-PCD in wt cells, by scavenging H(2)O(2) and by inhibiting both cyt c release and caspase-like activation. This shows the occurrence of a reactive oxygen species (ROS)-dependent AA-PCD. Contrarily no NAC dependent change in AA-PCD of mutant cells was detectable, showing that a ROS-independent AA-PCD can also occur.

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Osmoregulated trehalose-derived oligosaccharides in Sinorhizobium meliloti.

Publication Date: 2010 Aug 20 PMID: 20674571
Authors: Brique, A. - Devassine, J. - Pilard, S. - Cailleu, D. - Gosselin, I.
Journal: FEBS Lett

Sinorhizobium meliloti is a soil bacterium accumulating glutamate, N-acetylglutaminyl glutamine amide and trehalose in hyperosmolarity. Besides these compatible solutes, we highlighted several compounds in S. meliloti Rm1021 wild-type strain. The purification and the structural characterization based on liquid chromatography evaporative light scattering detector, electrospray ionization high resolution mass spectrometry and nuclear magnetic resonance techniques showed they were four linear oligosaccharides composed of 3, 4, 5 and 6 glucose units all linked by alpha-(1-->2) linkages except a terminal alpha-(1<-->1) linkage. These oligosaccharides were cytoplasmic and were observed in several wild-type strains suggesting they were common features in S. meliloti strains grown in hyperosmolarity.

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Editorial.

Publication Date: 2010 Aug 3 PMID: 20674570
Authors:
Journal: FEBS Lett

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Nucleosome deposition and DNA methylation may participate in the recognition of premature termination codon in nonsense-mediated mRNA decay.

Publication Date: 2010 Aug 20 PMID: 20674569
Authors: Niu, D. K. - Cao, J. L.
Journal: FEBS Lett

In non-mammalian eukaryotes, an abnormally long 3' untranslated region (UTR) is generally thought to be the definitive signal in the recognition of a premature termination codon (PTC) in nonsense-mediated mRNA decay (NMD). However, because the lengths of 3' UTRs in normal mRNAs are widely distributed, "abnormally long" is hard to define. Distinct peaks of nucleosome deposition and DNA methylation have recently been found at coding region boundaries. We propose that nucleosomes and DNA methylation just upstream of a normal stop codon are ideal indicators for the position of a normal stop codon and may thus serve as signals in PTC recognition.

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Generation of trans-mitochondrial mito-mice by the introduction of a pathogenic G13997A mtDNA from highly metastatic lung carcinoma cells.

Publication Date: 2010 Aug 3 PMID: 20674568
Authors: Yokota, M. - Shitara, H. - Hashizume, O. - Ishikawa, K. - Nakada, K. - Ishii, R. - Taya, C. - Takenaga, K. - Yonekawa, H. - Hayashi, J. I.
Journal: FEBS Lett

To investigate the effects of respiration defects on the disease phenotypes, we generated trans-mitochondrial mice (mito-mice) by introducing a mutated G13997A mtDNA, which specifically induces respiratory complex I defects and metastatic potentials in mouse tumor cells. First, we obtained ES cells and chimeric mice containing the G13997A mtDNA, and then we generated mito-mice carrying the G13997A mtDNA via its female germ line transmission. The three-month-old mito-mice showed complex I defects and lactate overproduction, but showed no other phenotypes related to mitochondrial diseases or tumor formation, suggesting that aging or additional nuclear abnormalities are required for expression of other phenotypes.

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Maintenance of red blood cell integrity by AMP-activated protein kinase alpha1 catalytic subunit.

Publication Date: 2010 Aug 20 PMID: 20670625
Authors: Foretz, M. - Guihard, S. - Leclerc, J. - Fauveau, V. - Couty, J. P. - Andris, F. - Gaudry, M. - Andreelli, F. - Vaulont, S. - Viollet, B.
Journal: FEBS Lett

AMP-activated protein kinase (AMPK) plays a pivotal role in regulating cellular energy metabolism. We previously showed that AMPKalpha1-/- mice develop moderate anemia associated with splenomegaly and high reticulocytosis. Here, we report that splenectomy of AMPKalpha1-/- mice worsened anemia supporting evidence that AMPKalpha1-/- mice developed a compensatory response through extramedullary erythropoiesis in the spleen. Transplantation of bone marrow from AMPKalpha1-/- mice into wild-type recipients recapitulated the hematologic phenotype. Further, AMPKalpha1-/- red blood cells (RBC) showed less deformability in response to shear stress limiting their membrane flexibility. Thus, our results highlight the crucial role of AMPK to preserve RBC integrity.

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Insulin modulates induction of glucose-regulated protein 78 during endoplasmic reticulum stress via augmentation of ATF4 expression in human neuroblastoma cells.

Publication Date: 2010 Aug 20 PMID: 20667453
Authors: Inageda, K.
Journal: FEBS Lett

The effect of insulin on endoplasmic reticulum (ER) stress was investigated. Insulin protected cell death induced by ER stress and increased glucose-regulated protein 78 (GRP78) mRNA and protein levels. Insulin also significantly increased activating transcription factor-4 (ATF4) protein in the nucleus, which was inhibited by LY294002, a phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor. The increase of ATF4 protein by insulin was not due to transcriptional or translational up-regulation but to a post-translational mechanism. Knockdown of ATF4 by siRNA significantly inhibited GRP78 induction by insulin. These results indicate that insulin modulated ER stress-induced GRP78 expression occurs via ATF4 up-regulation.

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The oocyte-specific transcription factor, Nobox, regulates the expression of Pad6, a peptidylarginine deiminase in the oocyte.

Publication Date: 2010 Aug 20 PMID: 20659469
Authors: Choi, M. - Lee, O. H. - Jeon, S. - Park, M. - Lee, D. R. - Ko, J. J. - Yoon, T. K. - Rajkovic, A. - Choi, Y.
Journal: FEBS Lett

Nobox is an oocyte-specific transcriptional regulator. Nobox deficiency disrupts early folliculogenesis and the expression of oocyte-specific genes in mice. In the present study, we found that peptidylarginine deiminase 6 (Pad6) was downregulated in Nobox-null ovaries. Pad6 is preferentially expressed in oocytes and its transcript is detectable at embryonic day 16.5. In addition, we identified one Nobox DNA-binding element (NBE) within the mouse Pad6 promoter. The NBE includes a core sequence TAATTA. Sequence-specific binding of Nobox to the TAATTA motif was confirmed. Nobox overexpression augmented transcriptional activity of a luciferase reporter driven by mouse Pad6. Our findings indicate that Nobox is a critical regulator that orchestrates oocyte-specific genes such as Pad6 during folliculogenesis.

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From phenotype to gene: Detecting disease-specific gene functional modules via a text-based human disease phenotype network construction.

Publication Date: 2010 Aug 20 PMID: 20659468
Authors: Zhang, S. H. - Wu, C. - Li, X. - Chen, X. - Jiang, W. - Gong, B. S. - Li, J. - Yan, Y. Q.
Journal: FEBS Lett

Currently, some efforts have been devoted to the text analysis of disease phenotype data, and their results indicated that similar disease phenotypes arise from functionally related genes. These related genes work together, as a functional module, to perform a desired cellular function. We constructed a text-based human disease phenotype network and detected 82 disease-specific gene functional modules, each corresponding to a different phenotype cluster, by means of graph-based clustering and mapping from disease phenotype to gene. Since genes in such gene functional modules are functionally related and cause clinically similar diseases, they may share common genetic origin of their associated disease phenotypes. We believe the investigation may facilitate the ultimate understanding of the common pathophysiologic basis of associated diseases.

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Transcription factor activator protein-2beta accelerates lipid accumulation in macrophages via enhancing the transcription of CD36.

Publication Date: 2010 Aug 20 PMID: 20659467
Authors: Gan, L. - Zhu, D. - Ding, Z.
Journal: FEBS Lett

The role of transcription factor activator protein-2beta (AP-2beta) in foam cell formation was investigated. Uptake assay of DiI-labeled oxidized low density lipoprotein and the lipid quantitative analysis by high performance liquid chromatography showed AP-2beta promoted the lipid accumulation. The quantitative real-time RT-PCR and Western blot indicated that AP-2beta upregulated the expression of CD36. Luciferase assay, electrophoretic mobility shift assay and chromatin immunoprecipitation confirmed that AP-2beta bound to AP-2 binding sites in CD36 promoter region and enhanced the promoter activity of CD36 gene. We conclude that AP-2beta may function in foam cell formation through enhancing the transcription and expression of CD36 followed by increased lipid uptake.

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Malfolded recombinant Tat substrates are Tat-independently degraded in Escherichia coli.

Publication Date: 2010 Aug 20 PMID: 20659466
Authors: Lindenstrauss, U. - Matos, C. F. - Graubner, W. - Robinson, C. - Bruser, T.
Journal: FEBS Lett

The twin-arginine translocation (Tat) system translocates folded proteins across biological membranes. It has been suggested that the Tat system of Escherichia coli can direct Tat substrates to degradation if they are not properly folded [Matos, C.F., Robinson, C. and Di Cola, A. (2008) The Tat system proofreads FeS protein substrates and directly initiates the disposal of rejected molecules. EMBO J. 27, 2055-2063; Matos, C.F., Di Cola, A. and Robinson, C. (2009) TatD is a central component of a Tat translocon-initiated quality control system for exported FeS proteins in Escherichia coli. EMBO Rep. 10, 474-479]. Contrary to the earlier reports, it is now concluded that reported differences between tested strains were due to variations in expression levels and inclusion body formation. Using the native Tat substrate NrfC and a malfolded variant thereof, we show that the turnover of these proteins is not affected by the absence of all known Tat components. Malfolded NrfC is degraded more quickly than the native protein, indicating that Tat-independent protease systems can recognize malfolded Tat substrates.

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Ezetimibe stimulates faecal neutral sterol excretion depending on abcg8 function in mice.

Publication Date: 2010 Aug 20 PMID: 20659465
Authors: Jakulj, L. - Vissers, M. N. - van Roomen, C. P. - van der Veen, J. N. - Vrins, C. L. - Kunne, C. - Stellaard, F. - Kastelein, J. J. - Groen, A. K.
Journal: FEBS Lett

Ezetimibe stimulates faecal neutral sterol (FNS) excretion in mice, which cannot be explained by cholesterol absorption inhibition alone. We investigated whether these effects are mediated via the sterol exporter ATP binding cassette transporter G8 (abcg8). Ezetimibe increased FNS excretion 2.7-fold in WT mice and 1.5-fold in abcg8(-/-) mice, without affecting biliary cholesterol secretion. Daily FNS excretion exceeded the sum of dietary cholesterol intake and biliary secretion by about 60%. Ezetimibe enhanced this 'extra' FNS excretion by 3.5-fold and 1.5-fold in wildtype (WT) and abcg8(-/-) mice, respectively. Ezetimibe stimulates fecal sterol excretion of non-biliary and non-dietary origin, probably through stimulation of trans-intestinal cholesterol excretion. We show that this effect depends on intact abcg8 function.

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Trigger factor lacking the PPIase domain can enhance the folding of eukaryotic multi-domain proteins in Escherichia coli.

Publication Date: 2010 Aug 20 PMID: 20659464
Authors: Gupta, R. - Lakshmipathy, S. K. - Chang, H. C. - Etchells, S. A. - Hartl, F. U.
Journal: FEBS Lett

Recombinant expression of eukaryotic proteins in bacteria often results in misfolding and aggregation. The ribosome-binding Trigger factor (TF) is the first molecular chaperone that interacts with nascent polypeptide chains in bacteria. Here we show that mutant TF lacking the PPIase domain (TFNC) is more efficient than wild-type TF in enhancing the folding yield of multi-domain proteins such as firefly luciferase. We find that TFNC has a shorter residence time on nascent chains, thus facilitating co-translational folding. By delaying folding relative to translation, the PPIase domain may increase the propensity of misfolding for certain eukaryotic proteins that rely on a mechanism of co-translational, domain-wise folding.

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The Drosophila homolog of methionine sulfoxide reductase A extends lifespan and increases nuclear localization of FOXO.

Publication Date: 2010 Aug 20 PMID: 20655917
Authors: Chung, H. - Kim, A. K. - Jung, S. A. - Kim, S. W. - Yu, K. - Lee, J. H.
Journal: FEBS Lett

Methionine sulfoxide reductase A (msrA) was previously found to increase resistance to oxidative stress and longevity in animals. We identified Drosophila msrA (dmsrA), a Drosophila homolog of human msrA, as a downstream effector of forkhead box O (FOXO) signaling in Drosophila, which enhances resistance to oxidative stress and increases survival under stressed conditions. Additionally, overexpression of dmsrA in neurons extended the lifespan of flies. Moreover, overexpression of dmsrA in fat body cells caused FOXO to translocate to the nucleus, implying that this possible positive feedback loop between dmsrA and FOXO could potentiate the antioxidant activity of dmsrA and increase the lifespan in Drosophila.

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TERRA biogenesis, turnover and implications for function.

Publication Date: 2010 Sep 10 PMID: 20655916
Authors: Feuerhahn, S. - Iglesias, N. - Panza, A. - Porro, A. - Lingner, J.
Journal: FEBS Lett

Telomeres are heterochromatic structures at the ends of eukaryotic chromosomes. As other heterochromatin regions, telomeres are transcribed, from the subtelomeric region towards chromosome ends into the long non-coding RNA TERRA. Telomere transcription is a widespread phenomenon as it has been observed in species belonging to several kingdoms of the eukaryotic domain. TERRA is part of telomeric heterochromatin in addition to being present in the nucleoplasm. Here, we review the current knowledge of TERRA structure, biogenesis and turnover. In addition, we discuss presumed roles of this RNA during replication of telomeric DNA, heterochromatin formation and the regulation of telomerase.

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Telomere biology in Metazoa.

Publication Date: 2010 Sep 10 PMID: 20655915
Authors: Gomes, N. M. - Shay, J. W. - Wright, W. E.
Journal: FEBS Lett

In this review we present critical overview of some of the available literature on the fundamental biology of telomeres and telomerase in Metazoan. With the exception of Nematodes and Arthropods, the (TTAGGG)(n) sequence is conserved in most Metazoa. Available data show that telomerase-based end maintenance is a very ancient mechanism in unicellular and multicellular organisms. In invertebrates, fish, amphibian, and reptiles persistent telomerase activity in somatic tissues might allow the maintenance of the extensive regenerative potentials of these species. Telomerase repression among birds and many mammals suggests that, as humans, they may use replicative aging as a tumor protection mechanism.

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Galectin-3 secreted by human umbilical cord blood-derived mesenchymal stem cells reduces amyloid-beta42 neurotoxicity in vitro.

Publication Date: 2010 Aug 20 PMID: 20655311
Authors: Kim, J. Y. - Kim, D. H. - Kim, D. S. - Kim, J. H. - Jeong, S. Y. - Jeon, H. B. - Lee, E. H. - Yang, Y. S. - Oh, W. - Chang, J. W.
Journal: FEBS Lett

In this study, we found that expression and secretion of galectin-3 (GAL-3) were upregulated by amyloid-beta42 (Abeta42) exposure in human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) without cell death. Abeta42-exposed rat primary cortical neuronal cells co-treated with recombinant GAL-3 were protected from neuronal death in a dose-dependent manner. hUCB-MSCs were cocultured with Abeta42-exposed rat primary neuronal cells or the neuroblastoma cell line, SH-SY5Y in a Transwell chamber. Coculture of hUCB-MSCs reduced cell death of Abeta42-exposed neurons and SH-SY5Y cells. This neuroprotective effect of hUCB-MSCs was reduced significantly by GAL-3 siRNA. These data suggested that hUCB-MSC-derived GAL-3 is a survival factor against Abeta42 neurotoxicity.

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Telomere biology and DNA repair: enemies with benefits.

Publication Date: 2010 Sep 10 PMID: 20655310
Authors: de Lange, T.
Journal: FEBS Lett

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The MRN complex in double-strand break repair and telomere maintenance.

Publication Date: 2010 Sep 10 PMID: 20655309
Authors: Lamarche, B. J. - Orazio, N. I. - Weitzman, M. D.
Journal: FEBS Lett

Genomes are subject to constant threat by damaging agents that generate DNA double-strand breaks (DSBs). The ends of linear chromosomes need to be protected from DNA damage recognition and end-joining, and this is achieved through protein-DNA complexes known as telomeres. The Mre11-Rad50-Nbs1 (MRN) complex plays important roles in detection and signaling of DSBs, as well as the repair pathways of homologous recombination (HR) and non-homologous end-joining (NHEJ). In addition, MRN associates with telomeres and contributes to their maintenance. Here, we provide an overview of MRN functions at DSBs, and examine its roles in telomere maintenance and dysfunction.

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miR-1/miR-206 regulate Hsp60 expression contributing to glucose-mediated apoptosis in cardiomyocytes.

Publication Date: 2010 Aug 20 PMID: 20655308
Authors: Shan, Z. X. - Lin, Q. X. - Deng, C. Y. - Zhu, J. N. - Mai, L. P. - Liu, J. L. - Fu, Y. H. - Liu, X. Y. - Li, Y. X. - Zhang, Y. Y. - Lin, S. G. - Yu, X. Y.
Journal: FEBS Lett

Hsp60 is an important component of defense mechanisms against diabetic myocardial injury; however, the cause of Hsp60 reduction in the diabetic myocardium remains unknown. After stimulation of cardiomyocytes with high glucose in vivo and in vitro, significant up-regulation of miR-1/miR-206 and post-transcriptional modulation of Hsp 60 were observed. Serum response factor (SRF) and the MEK1/2 pathway were involved in miR-1 and miR-206 expression in cardiomyocytes. miR-1 and miR-206 regulated Hsp60 expression post-transcriptionally and accelerated cardiomyocyte apoptosis through Hsp60. These results revealed that miR-1 and miR-206 regulate Hsp60 expression, contributing to high glucose-mediated apoptosis in cardiomyocytes.

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The 'true' L-xylulose reductase of filamentous fungi identified in Aspergillus niger.

Publication Date: 2010 Aug 20 PMID: 20654618
Authors: Mojzita, D. - Vuoristo, K. - Koivistoinen, O. M. - Penttila, M. - Richard, P.
Journal: FEBS Lett

L-Xylulose reductase is part of the eukaryotic pathway for l-arabinose catabolism. A previously identified L-xylulose reductase in Hypocrea jecorina turned out to be not the 'true' one since it was not upregulated during growth on L-arabinose and the deletion strain showed no reduced L-xylulose reductase activity but instead lost the D-mannitol dehydrogenase activity. In this communication we identified the 'TRUE'L-xylulose reductase in Aspergillus niger. The gene, lxrA (JGI177736), is upregulated on L-arabinose and the deletion results in a strain lacking the NADPH-specific L-xylulose reductase activity and having reduced growth on l-arabinose. The purified enzyme had a K(m) for L-xylulose of 25 mM and a nu(max) of 650 U/mg.

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The plastid hexokinase pHXK: A node of convergence for sugar and plastid signals in Arabidopsis.

Publication Date: 2010 Aug 20 PMID: 20650273
Authors: Zhang, Z. W. - Yuan, S. - Xu, F. - Yang, H. - Zhang, N. H. - Cheng, J. - Lin, H. H.
Journal: FEBS Lett

The inhibitors to plastid gene expression (PGE) were effective in preventing nuclear photosynthetic gene expression only if applied within the first 2-3 days of Arabidopsis seedling development. However, the signal transduction processes are still unknown. In this investigation, we found 3% glucose with 1mM chloramphenicol co-treatment repressed LHCB transcript significantly in mature Arabidopsis seedlings, while effective solo glucose treatment needed a concentration of 7%. The repressive effects of glucose and chloramphenicol on LHCB expression were inhibited in phxk (plastid hexokinase) mutant. pHXK enzyme activities, location, function in signal transduction, and cross talk to plastid GUN1 protein (a key signaling factor) were also investigated. The data suggest that pHXK may be a node of convergence for sugar-mediated and PGE-derived signals in Arabidopsis.

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3'-5' tRNAHis guanylyltransferase in bacteria.

Publication Date: 2010 Aug 20 PMID: 20650272
Authors: Heinemann, I. U. - Randau, L. - Tomko, R. J. Jr - Soll, D.
Journal: FEBS Lett

The identity of the histidine specific transfer RNA (tRNA(His)) is largely determined by a unique guanosine residue at position -1. In eukaryotes and archaea, the tRNA(His) guanylyltransferase (Thg1) catalyzes 3'-5' addition of G to the 5'-terminus of tRNA(His). Here, we show that Thg1 also occurs in bacteria. We demonstrate in vitro Thg1 activity for recombinant enzymes from the two bacteria Bacillus thuringiensis and Myxococcus xanthus and provide a closer investigation of several archaeal Thg1. The reaction mechanism of prokaryotic Thg1 differs from eukaryotic enzymes, as it does not require ATP. Complementation of a yeast thg1 knockout strain with bacterial Thg1 verified in vivo activity and suggests a relaxed recognition of the discriminator base in bacteria.

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Apigenin inhibits larval growth of Caenorhabditis elegans through DAF-16 activation.

Publication Date: 2010 Aug 20 PMID: 20647014
Authors: Kawasaki, I. - Jeong, M. H. - Oh, B. K. - Shim, Y. H.
Journal: FEBS Lett

Treatment of Caenorhabditis elegans with apigenin, 5,7,4'-trihydroxyflavone, induces larval growth inhibition. To understand the molecular basis of apigenin-induced larval growth inhibition, the effects of apigenin on DAF-16 activity were examined. DAF-16 was activated through nuclear translocation and the mRNA level of sod-3, one of the known DAF-16 target genes, was increased upon apigenin treatment. DAF-16 activity was required for the growth inhibition, since the larval growth retardation upon apigenin treatment was suppressed in daf-16 mutants. These results indicate that apigenin acts as a stressor that activates DAF-16, which in turn inhibits larval growth.

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beta-Arrestin 2-mediated heterologous desensitization of IGF-IR by prolonged exposure of SH-SY5Y neuroblastoma cells to a mu opioid agonist.

Publication Date: 2010 Aug 20 PMID: 20643133
Authors: Sparta, A. - Baiula, M. - Campbell, G. - Spampinato, S.
Journal: FEBS Lett

Prolonged (12h) exposure of SH-SY5Y neuroblastoma cells to the mu-opioid receptor (MOPr) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) causes homologous desensitization as well as heterologous desensitization of the extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation induced by insulin-like growth factor (IGF)-I. Brief (15 min) but not prolonged exposure to DAMGO transregulates the insulin-like growth factor-I (IGF-I) receptor, as evidenced by its phosphorylation in the absence of IGF-I. Silencing of beta-arrestin 2 uncouples the crosstalk between the two receptors, thus maintaining IGF-I-mediated receptor phosphorylation and ERK 1/2 activation even after prolonged DAMGO exposure. Furthermore, MOPr-induced activation of IGF-I receptor requires the tyrosine kinase c-Src.

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Tudor-SN interacts with and co-localizes with G3BP in stress granules under stress conditions.

Publication Date: 2010 Aug 20 PMID: 20643132
Authors: Gao, X. - Ge, L. - Shao, J. - Su, C. - Zhao, H. - Saarikettu, J. - Yao, X. - Yao, Z. - Silvennoinen, O. - Yang, J.
Journal: FEBS Lett

SGs are mRNA containing cytoplasmic structures that are assembled in response to stress. Tudor-SN protein is a ubiquitously expressed protein. Here, Tudor-SN protein was found to physiologically interact with G3BP, which is the marker and effector of SG. The kinetics of the assembly of SGs in the living cells demonstrated that Tudor-SN co-localizes with G3BP and is recruited to the same SGs in response to different stress stimuli. Knockdown of endogenous Tudor-SN did not inhibit the formation of SGs, but retarded the aggregation of small SGs into large SGs. Thus Tudor-SN may not be an initiator as essential as G3BP for the formation of SGs, but affects the aggregation of SGs. These findings identify Tudor-SN as a novel component of SGs.

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Multiple recognition systems adopting four different glycotopes at the same domain for the Agaricus bisporus agglutinin-glycan interactions.

Publication Date: 2010 Aug 20 PMID: 20643131
Authors: Wu, A. M. - Liu, J. H. - Gong, Y. P. - Li, C. C. - Chang, E. T.
Journal: FEBS Lett

For the GalNAcalpha1--> specific Agaricus bisporus agglutinin (ABA) from an edible mushroom, the mechanism of polyvalent Galbeta1-->3/4GlcNAcbeta1--> complex in ABA-carbohydrate recognition has not been well defined since Gal and GlcNAc are weak ligands. By enzyme-linked lectinosorbent and inhibition assays, we show that the polyvalent Galbeta1-->3/4GlcNAcbeta1--> in natural glycans also play vital roles in binding and we propose that four different intensities of glycotopes (Galbeta1-3GalNAcalpha1-, GalNAcalpha1-Ser/Thr and Galbeta1-3/4GlcNAcbeta1-) construct three recognition systems at the same domain. This peculiar concept provides the most comprehensive mechanism for the attachment of ABA to target glycans and malignant cells at the molecular level.

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Interaction of human immunodeficiency virus gp120 with the voltage-gated potassium channel BEC1.

Publication Date: 2010 Aug 20 PMID: 20638388
Authors: Herrmann, M. - Ruprecht, K. - Sauter, M. - Martinez, J. - van Heteren, P. - Glas, M. - Best, B. - Meyerhans, A. - Roemer, K. - Mueller-Lantzsch, N.
Journal: FEBS Lett

Retrovirus replication critically depends on a dynamic interplay between retroviral and host proteins. We report on the binding of the surface subunit (glycoprotein 120 (gp120)) of the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) to the cytoplasmic C-terminus of the voltage-gated potassium channel BEC1 (brain-specific ether-a-go-go-like channel 1), an interaction that can result in the repression of BEC's activity and the inhibition of HIV-1 particle-release. BEC1 protein was found to be expressed in T cells and macrophages, the major target cells of HIV-1. Thus, gp120/BEC1 interaction may be involved in HIV-1 life cycle and/or pathogenesis.

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Activation of Snake in a serine protease cascade that defines the dorsoventral axis is atypical and pipe-independent in Drosophila embryos.

Publication Date: 2010 Aug 20 PMID: 20638387
Authors: Steen, P. W. - Tian, S. - Tully, S. E. - Cravatt, B. F. - LeMosy, E. K.
Journal: FEBS Lett

During Drosophila embryogenesis, establishment of ventral and lateral cell fates requires spatial regulation of an extracellular serine protease cascade composed of Nudel, Gastrulation Defective (GD), Snake, and Easter. Pipe, a sulfotransferase expressed ventrally during oogenesis, sulfates secreted targets that somehow confer positive spatial input to this cascade. Nudel and GD activation are pipe-independent, while Easter activation requires pipe. The effect of pipe on Snake activation has been unknown. Here we show that Snake activation is cascade-dependent but pipe-independent. These findings support a conclusion that Snake's activation of Easter is the first spatially regulated step in the dorsoventral protease cascade.

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Crystal structure of tubulin folding cofactor A from Arabidopsis thaliana and its beta-tubulin binding characterization.

Publication Date: 2010 Aug 20 PMID: 20638386
Authors: Lu, L. - Nan, J. - Mi, W. - Li, L. F. - Wei, C. H. - Su, X. D. - Li, Y.
Journal: FEBS Lett

Microtubules are composed of polymerized alpha/beta-tubulin heterodimers. Biogenesis of assembly-competent tubulin dimers is a complex multistep process that requires sequential actions of distinct molecular chaperones and cofactors. Tubulin folding cofactor A (TFCA), which captures beta-tubulin during the folding pathway, has been identified in many organisms. Here, we report the crystal structure of Arabidopsis thaliana TFC A (KIESEL, KIS), which forms a monomeric three-helix bundle. The functional binding analysis demonstrated that KIS interacts with beta-tubulin in plant. Furthermore, mutagenesis studies indicated that the alpha-helical regions of KIS participate in beta-tubulin binding. Unlike the budding yeast TFC A, the two loop regions of KIS are not required for this interaction suggesting a distinct binding mechanism of TFC A to beta-tubulin in plants.

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Interaction of Beclin 1 with survivin regulates sensitivity of human glioma cells to TRAIL-induced apoptosis.

Publication Date: 2010 Aug 20 PMID: 20638385
Authors: Niu, T. K. - Cheng, Y. - Ren, X. - Yang, J. M.
Journal: FEBS Lett

We reported a novel interaction between Beclin 1, a key regulator of autophagy, and survivin, a member of the inhibitor of apoptosis protein family. We found that knock-down of Beclin 1 down-regulated survivin protein, and the turnover rate of survivin was increased when Beclin 1 expression was silenced. Knock-down of Beclin 1 sensitized glioma cells to TRAIL-induced apoptosis, and introduction of survivin antagonized the sensitizing effect, suggesting that down-regulation of survivin mediates the enhanced sensitivity to TRAIL-induced apoptosis. These results demonstrate a novel interaction between Beclin 1 and survivin, and may provide a potential mechanism underlying the cross-talk between autophagy and apoptosis.

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Alpha-synuclein induced cell death in mouse hippocampal (HT22) cells is mediated by nitric oxide-dependent activation of caspase-3.

Publication Date: 2010 Aug 4 PMID: 20638384
Authors: Adamczyk, A. - Kazmierczak, A. - Czapski, G. A. - Strosznajder, J. B.
Journal: FEBS Lett

Our previous studies indicated that exogenous alpha-synuclein (ASN) activates neuronal nitric oxide (NO) synthase (nNOS) in rat brain slices. The present study, carried out on immortalized hippocampal neuronal cells (HT22), was designed to extend the previous results by showing the molecular pathway of NO-mediated cell death induced by exogenous ASN. Extracellular ASN (10 microM) was found to stimulate nitric oxide synthase (NOS) and increase caspase-3 activity in HT22 cells, leading to poly(ADP-ribose) polymerase (PARP-1) cleavage. The inhibitor of Ca2+-dependent NOS (N-nitro-L-arginine, 100 microM) prevented ASN-evoked caspase-3 activation and PARP-1 degradation. ASN exposure resulted in apoptotic death of HT22 cells and this effect was reversed by inhibition of NO synthesis and caspase-3 activity. Our results demonstrated that extracellular ASN induces neuronal cell death by NO-mediated caspase-3 activation.

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AMPK beta subunits display isoform specific affinities for carbohydrates.

Publication Date: 2010 Aug 4 PMID: 20637197
Authors: Koay, A. - Woodcroft, B. - Petrie, E. J. - Yue, H. - Emanuelle, S. - Bieri, M. - Bailey, M. F. - Hargreaves, M. - Park, J. T. - Park, K. H. - Ralph, S. - Neumann, D. - Stapleton, D. - Gooley, P. R.
Journal: FEBS Lett

AMP-activated protein kinase (AMPK) is a heterotrimer of catalytic (alpha) and regulatory (beta and gamma) subunits with at least two isoforms for each subunit. AMPK beta1 is widely expressed whilst AMPK beta2 is highly expressed in muscle and both beta isoforms contain a mid-molecule carbohydrate-binding module (beta-CBM). Here we show that beta2-CBM has evolved to contain a Thr insertion and increased affinity for glycogen mimetics with a preference for oligosaccharides containing a single alpha-1,6 branched residue. Deletion of Thr-101 reduces affinity for single alpha-1,6 branched oligosaccharides by 3-fold, while insertion of this residue into the equivalent position in the beta1-CBM sequence increases affinity by 3-fold, confirming the functional importance of this residue.

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Telomeres: structures in need of unwinding.

Publication Date: 2010 Sep 10 PMID: 20637196
Authors: Paeschke, K. - McDonald, K. R. - Zakian, V. A.
Journal: FEBS Lett

Telomeres protect the ends of eukaryotic chromosomes from being recognized and processed as double strand breaks. In most organisms, telomeric DNA is highly repetitive with a high GC-content. Moreover, the G residues are concentrated in the strand running 3'-5' from the end of the chromosome towards its center. This G-rich strand is extended to form a 3' single-stranded tail that can form unusual secondary structures such as T-loops and G-quadruplex DNA. Both the duplex repeats and the single-stranded G-tail are assembled into stable protein-DNA complexes. The unique architecture, high GC content, and multi-protein association create particularly stable protein-DNA complexes that are a challenge for replication, recombination, and transcription. Helicases utilize the energy of nucleotide hydrolysis to unwind base paired nucleic acids and, in some cases, to displace proteins from them. The telomeric functions of helicases from the RecQ, Pifl, FANCJ, and DNA2 families are reviewed in this article. We summarize data showing that perturbation of their telomere activities can lead to telomere dysfunction and genome instability and in some cases human disease.

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Redox regulation of the tumor suppressor PTEN by glutathione.

Publication Date: 2010 Aug 20 PMID: 20637195
Authors: Kim, Y. - Song, Y. B. - Kim, T. Y. - Kim, I. - Han, S. J. - Ahn, Y. - Cho, S. H. - Choi, C. Y. - Chay, K. O. - Yang, S. Y. - Ahn, B. W. - Huh, W. K. - Lee, S. R.
Journal: FEBS Lett

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expressed in Saccharomyces cerevisiae was reversibly oxidized by hydrogen peroxide and reduced by cellular reductants. Reduction of hPTEN was delayed in each of S. cerevisiae gsh1Delta and gsh2Delta mutants. Expression of gamma-glutamylcysteine synthetase Gsh1 in the gsh1Delta mutant rescued regeneration rate of hPTEN. Oxidized hPTEN was reduced by glutathione in a concentration- and time-dependent manner. Glutathionylated PTEN was detected. Incubation of 293T cells with BSO and knockdown expression of GCLc in HeLa cells by siRNA resulted in the delay of reduction of oxidized PTEN. Also, in HeLa cells transfected with GCLc siRNA, stimulation with epidermal growth factor resulted in the increase of oxidized PTEN and phosphorylation of Akt. These results suggest that the reduction of oxidized hPTEN is mediated by glutathione.

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Calcium regulation of the ATPase activity of Physarum and scallop myosins using hybrid smooth muscle myosin: the role of the essential light chain.

Publication Date: 2010 Aug 4 PMID: 20633559
Authors: Zhang, Y. - Nakamura, A. - Kawamichi, H. - Yoshiyama, S. - Katayama, T. - Kohama, K.
Journal: FEBS Lett

To examine the role of two light chains (LCs) of the myosin II on Ca2+ regulation, we produced hybrid heavy meromyosin (HMM) having LCs from Physarum and/or scallop myosin using the smooth muscle myosin heavy chain. Ca2+ inhibited motility and ATPase activity of hybrid HMMs with LCs from Physarum myosin but activated those of hybrid HMM with LCs from scallop myosin, indicating an active role of LCs. ATPase activity of hybrid HMMs with LCs from different species showed the same effect by Ca2+ even though they did not support motility. Our results suggest that communication between the original combinations of LC is important for the motor function.

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Tropomyosin-binding properties of the CHASM protein are dependent upon its calponin homology domain.

Publication Date: 2010 Aug 4 PMID: 20627103
Authors: Ulke-Lemee, A. - Ishida, H. - Borman, M. A. - Valderrama, A. - Vogel, H. J. - MacDonald, J. A.
Journal: FEBS Lett

The calponin homology-associated smooth muscle protein (CHASM) can modulate muscle contractility, and its biological action may involve an interaction with the contractile filament. In this study, we demonstrate an interaction between CHASM and tropomyosin. Deletion constructs of CHASM were generated, and pull-down assays revealed a minimal deletion construct that could bind tropomyosin. Removal of the calponin homology (CH) domain or expression of the CH domain alone did not enable binding. The interaction was characterized by microcalorimetry with a dissociation constant of 2.0x10(-6) M. Confocal fluorescence microscopy also showed green fluorescent protein (GFP)-CHASM localization to filamentous structures within smooth muscle cells, and this targeting was dependent upon the CH domain.

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Direct interaction and functional coupling between voltage-gated CaV1.3 Ca2+ channel and GABAB receptor subunit 2.

Publication Date: 2010 Aug 4 PMID: 20627102
Authors: Park, H. W. - Jung, H. - Choi, K. H. - Baik, J. H. - Rhim, H.
Journal: FEBS Lett

Although CaV1.2 and CaV1.3 are two subtypes of L-type Ca2+ channels expressed in the CNS, functions of CaV1.3 have not been well elucidated compared to CaV1.2. Here, we found that CaV1.3-NT associates with GABABR2-CT using yeast two-hybrid, GST pull-down and co-immunoprecipitation assays. We also demonstrated co-localization of CaV1.3 and GABABR2 in HEK293 cells and cultured hippocampal neurons. Whole-cell patch-clamp and Ca2+-imaging experiments revealed that activation of GABABR increases CaV1.3 currents and intracellular Ca2+ via CaV1.3, but not CaV1.2. These results show a physical and functional interaction between CaV1.3 and GABABR, suggesting the potential pivotal roles of CaV1.3 in the CNS.

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The fast-mobility isoform of mouse Mcl-1 is a mitochondrial matrix-localized protein with attenuated anti-apoptotic activity.

Publication Date: 2010 Aug 4 PMID: 20627101
Authors: Huang, C. R. - Yang-Yen, H. F.
Journal: FEBS Lett

The full-length pro-survival protein Mcl-1 predominantly resides on the outer membrane of mitochondria. Here, we identified a mitochondrial matrix-localized isoform of Mcl-1 that lacks 33 amino acid residues at the N-terminus which serve both as a mitochondrial targeting and processing signal. Ectopically-expressed Mcl-1 without the N-terminal 33 residues failed to enter the mitochondrial matrix but retained wt-like activities both for interaction with BH3-only proteins and anti-apoptosis. In contrast, the mitochondrial matrix-localized isoform failed to interact with BH3-only proteins and manifested an attenuated anti-apoptotic activity. This study reveals that import of Mcl-1 into the mitochondrial matrix results in the attenuation of Mcl-1's anti-apoptotic function.

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TFPI or uPA-PAI-1 complex affect cell function through expression variation of type II very low density lipoprotein receptor.

Publication Date: 2010 Aug 4 PMID: 20624392
Authors: Di, Y. - Liu, Z. - Tian, J. - Zong, Y. - Yang, P. - Qu, S.
Journal: FEBS Lett

Very low density lipoprotein receptors (VLDLR) including type I and type II are known to affect cell functions by binding to its extracellular ligands. However, the effect of these ligands on VLDLR expression remains elusive. Tissue factor pathway inhibitor (TFPI) and urokinase plasminogen activator and plasminogen activator inhibitor 1 (uPA-PAI-1) complex, two ligands of VLDLR, were used to examine their effects on VLDLR expression. TFPI treatment decreased type II VLDLR expression, inhibited cell proliferation and migration, and degradated beta-catenin in SGC7901 cells. However, uPA-PAI-1 complex, increased type II VLDLR expression with promoted cell proliferation and migration and stabilization of beta-catenin. These results indicated that extracellular ligands can change the expression of type II VLDLR to affect cell proliferation and migration.

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Elevation of cyclic AMP causes an imbalance between NF-kappaB and p53 in NALM-6 cells treated by doxorubicin.

Publication Date: 2010 Aug 4 PMID: 20624391
Authors: Safa, M. - Zand, H. - Mousavizadeh, K. - Kazemi, A. - Bakhshayesh, M. - Hayat, P.
Journal: FEBS Lett

We previously showed that cAMP can inhibit DNA damage-induced wild type p53 accumulation in human pre-B NALM-6 cells, leading to a profound reduction of their apoptotic response. Here, we provide evidence for the potentiation of DNA damage-induced NF-kappaB activation by cAMP. We found that inhibition of NF-kappaB activation prevents the inhibitory effect of cAMP on doxorubicin-induced apoptosis. Moreover, cAMP exerts its inhibitory effect on doxorubicin-induced apoptosis in a PKA-independent manner. The present study also shows that elevation of cAMP prolongs the phosphorylation of IkappaB and subsequent activation of NF-kappaB in doxorubicin treated NALM-6 cells in a proteasome-dependent manner. Taken together, our results demonstrate that cAMP abrogates the balance between apoptotic and antiapoptotic transcription factors that are hallmarks of DNA damage signaling.

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p38 MAPK pathway is involved in high glucose-induced thioredoxin interacting protein induction in mouse mesangial cells.

Publication Date: 2010 Aug 4 PMID: 20624390
Authors: Ren, Y. - Shi, Y. - Wang, Y. - Li, Y. - Wu, S. - Li, H. - Zhang, Y. - Duan, H.
Journal: FEBS Lett

Excessive reactive oxygen species (ROS) play a key role in the pathogenesis of diabetic nephropathy. The thioredoxin (TRX) system, a major thiol antioxidant system, regulates the reduction of intracellular ROS. Here we show that high glucose (HG) inhibits TRX ROS-scavenging function through p38 mitogen-activated protein kinase (MAPK)-mediated induction of thioredoxin interacting protein (TXNIP) in mouse mesangial cells (MMCs). Knockdown of TXNIP in MMCs reversed HG-induced reduction of TRX activity and inhibited HG-induced activation of p38 MAPK and increased synthesis of TGF-beta1 and fibronectin. These data suggest that HG-induced overexpression of TXNIP in MMCs, which may be via the p38 MAPK pathway.

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NLS-mediated NPC functions of the nucleoporin Pom121.

Publication Date: 2010 Aug 4 PMID: 20624389
Authors: Yavuz, S. - Santarella-Mellwig, R. - Koch, B. - Jaedicke, A. - Mattaj, I. W. - Antonin, W.
Journal: FEBS Lett

RanGTP mediates nuclear import and mitotic spindle assembly by dissociating import receptors from nuclear localization signal (NLS) bearing proteins. We investigated the interplay between import receptors and the transmembrane nucleoporin Pom121. We found that Pom121 interacts with importin alpha/beta and a group of nucleoporins in an NLS-dependent manner. In vivo, replacement of Pom121 with an NLS mutant version resulted in defective nuclear transport, induction of aberrant cytoplasmic membrane stacks and decreased cell viability. We propose that the NLS sites of Pom121 affect its function in NPC assembly both by influencing nucleoporin interactions and pore membrane structure.

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Upregulation of Bcl2 inhibits apoptosis-driven BAX insertion but favors BAX relocalization in mitochondria.

Publication Date: 2010 Aug 4 PMID: 20621101
Authors: Teijido, O. - Dejean, L.
Journal: FEBS Lett

Protein-protein interactions between the Bcl2 family proteins regulate apoptosis. An imbalance of this interaction network due to the upregulation of the proto-oncogene Bcl2 leads to a resistance to apoptosis associated with tumor formation. Bcl2 overexpression inhibits BAX oligomerization and mitochondrial outer membrane (MOM) permeabilization. However, Bcl2 effects on earlier steps of BAX-mediated apoptosis are not fully understood. Bcl2 overexpression inhibits BAX insertion into the MOM but spontaneously increases BAX relocalization to the mitochondria. Also, a physical interaction between BAX and Bcl2 is necessary for these two effects to occur. Taken together, these results suggest upregulated Bcl2 stabilizes BAX loose binding to mitochondrial membranes, inhibiting its insertion into the MOM and consequently cytochrome c release.

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SABP2, a methyl salicylate esterase is required for the systemic acquired resistance induced by acibenzolar-S-methyl in plants.

Publication Date: 2010 Aug 4 PMID: 20621100
Authors: Tripathi, D. - Jiang, Y. L. - Kumar, D.
Journal: FEBS Lett

Tobacco SABP2, a 29kDa protein catalyzes the conversion of methyl salicylic acid (MeSA) into salicylic acid (SA) to induce SAR. Pretreatment of plants with acibenzolar-S-methyl (ASM), a functional analog of salicylic acid induces systemic acquired resistance (SAR). Data presented in this paper suggest that SABP2 catalyzes the conversion of ASM into acibenzolar to induce SAR. Transgenic SABP2-silenced tobacco plants when treated with ASM, fail to express PR-1 proteins and do not induce robust SAR expression. When treated with acibenzolar, full SAR is induced in SABP2-silenced plants. These results show that functional SABP2 is required for ASM-mediated induction of resistance.

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Mutational deglycosylation of the Fc portion of immunoglobulin G causes O-sulfation of tyrosine adjacently preceding the originally glycosylated site.

Publication Date: 2010 Aug 4 PMID: 20621099
Authors: Masuda, K. - Yamaguchi, Y. - Takahashi, N. - Jefferis, R. - Kato, K.
Journal: FEBS Lett

Mutagenesis directed to a specific glycosylation site has been widely used to examine biological roles of individual glycans. However, occurrence of any post-translational modification on such deglycosylated mutants has not yet been well characterized. Here we performed mass spectrometric analyses of the Fc fragment of an unglycosylated mutant of mouse immunoglobulin G2b, whose conserved N-glycosylation site, i.e. Asn297, was substituted with alanine. We found that a major part of this mutant is sulfated at Tyr296, which adjacently precedes the originally glycosylated site. Our findings demonstrate that mutational deglycosylation can induce an unexpected post-translational modification in the protein.

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Origin of the pKa shift of the catalytic lysine in acetoacetate decarboxylase.

Publication Date: 2010 Aug 4 PMID: 20621098
Authors: Ishikita, H.
Journal: FEBS Lett

The pKa value of Lys115, the catalytic residue in acetoacetate decarboxylate, was calculated using atomic coordinates of the X-ray crystal structure with consideration of the protonation states of all titratable sites in the protein. The calculated pKa value of Lys115 (pKa(Lys115)) was unusually low (approximately 6) in agreement with the experimentally measured value. Although charged residues impact pKa(Lys115) considerably in the native protein, the significant pKa(Lys115) downshift in the protein with respect to aqueous solution was mainly due to loss of the solvation energy in the catalytic active site relative to bulk water.

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Transient and permanent gene transfer into the brain of the teleost fish medaka (Oryzias latipes) using human adenovirus and the Cre-loxP system.

Publication Date: 2010 Aug 20 PMID: 20621097
Authors: Suehiro, Y. - Kinoshita, M. - Okuyama, T. - Shimada, A. - Naruse, K. - Takeda, H. - Kubo, T. - Hashimoto, M. - Takeuchi, H.
Journal: FEBS Lett

In this study, we demonstrated that human type-5 adenovirus infected the brain of the teleost fish, medaka (Oryzias latipes), in vivo. Injection of adenoviral vector into the mesencephalic ventricle of medaka larvae induced the expression of reporter genes in some parts of the telencephalon, the periventricular area of the mesencephalon and diencephalon, and the cerebellum. Additionally, the Cre-loxP system works in medaka brains using transgenic medaka carrying a vector containing DsRed2, flanked by loxP sites under control of the beta-actin promoter and downstream promoterless enhanced green fluorescent protein (EGFP). We demonstrated that the presence of green fluorescence depended on injection of adenoviral vector expressing the Cre gene and confirmed that EGFP mRNA was transcribed in the virus-injected larvae.

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Deletion of Swm2p selectively impairs trimethylation of snRNAs by trimethylguanosine synthase (Tgs1p).

Publication Date: 2010 Aug 4 PMID: 20621096
Authors: Boon, K. L. - Kos, M.
Journal: FEBS Lett

The 5' cap trimethylation of small nuclear (snRNAs) and several nucleolar RNAs (snoRNAs) by trimethylguanosine synthase 1 (Tgs1p) is required for efficient pre-mRNA splicing. The previously uncharacterised protein Swm2p interacted with Tgs1p in yeast two-hybrid screens. In the present study we show that Swm2p interacts with the N-terminus of Tgs1p and its deletion impairs pre-mRNA splicing and pre-rRNA processing. The trimethylation of spliceosomal snRNAs and the U3 snoRNA, but not other snoRNAs, was abolished in the absence of Swm2p, indicating that Swm2p is required for a substrate-specific activity of Tgs1p.

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A novel splice variant of the human dicer gene is expressed in neuroblastoma cells.

Publication Date: 2010 Aug 4 PMID: 20615407
Authors: Potenza, N. - Papa, U. - Scaruffi, P. - Mosca, N. - Tonini, G. P. - Russo, A.
Journal: FEBS Lett

Dicer is a ribonuclease playing a key role in the biogenesis of microRNAs and small interfering RNAs. Here we report the identification of a novel splice variant of human dicer gene, the first one bearing a modified coding sequence. It encodes a truncated protein, t-Dicer that lacks the dsRNA-binding domain and is defective in one of the two RNase III catalytic centers. The splice variant was found in neuroblastoma cells and in cells induced to neuronal differentiation, whereas it was not detectable in other cell lines or in normal tissues. Interestingly, it occurred in primary neuroblastic tumors, mainly in stroma poor neuroblastomas.

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Crystal structure of leukotriene A4 hydrolase in complex with kelatorphan, implications for design of zinc metallopeptidase inhibitors.

Publication Date: 2010 Aug 4 PMID: 20609366
Authors: Tholander, F. - Roques, B. P. - Fournie-Zaluski, M. C. - Thunnissen, M. M. - Haeggstrom, J. Z.
Journal: FEBS Lett

Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the inflammatory process of mammals. It is an epoxide hydrolase and an aminopeptidase of the M1 family of the MA clan of Zn-metallopeptidases. We have solved the crystal structure of LTA4H in complex with N-[3(R)-[(hydroxyamino)carbonyl]-2-benzyl-1-oxopropyl]-L-alanine, a potent inhibitor of several Zn-metalloenzymes, both endopeptidases and aminopeptidases. The inhibitor binds along the sequence signature for M1 aminopeptidases, GXMEN. It exhibits bidentate chelation of the catalytic zinc and binds to LTA4H's enzymatically essential carboxylate recognition site. The structure gives clues to the binding of this inhibitor to related enzymes and thereby identifies residues of their S1' sub sites as well as strategies for design of inhibitors.

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Orientation of the axial ligands and magnetic properties of the hemes in the triheme ferricytochrome PpcA from G. sulfurreducens determined by paramagnetic NMR.

Publication Date: 2010 Aug 4 PMID: 20609365
Authors: Morgado, L. - Saraiva, I. H. - Louro, R. O. - Salgueiro, C. A.
Journal: FEBS Lett

The geometry of the axial ligands of the hemes in the triheme cytochrome PpcA from Geobacter sulfurreducens was determined in solution for the ferric form using the unambiguous assignment of the NMR signals of the alpha-substituents of the hemes. The paramagnetic 13C shifts of the hemes can be used to define the heme electronic structure, the geometry of the axial ligands, and the magnetic susceptibility tensor. The latter establishes the magnitude and geometrical dependence of the pseudocontact shifts, which are crucial to warrant reliable structural constraints for a detailed structural characterization of this paramagnetic protein in solution.

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Molecular simulations provide new insights into the role of the accessory immunoglobulin-like domain of Cel9A.

Publication Date: 2010 Aug 4 PMID: 20609364
Authors: Liu, H. - Pereira, J. H. - Adams, P. D. - Sapra, R. - Simmons, B. A. - Sale, K. L.
Journal: FEBS Lett

Cel9A from the thermoacidophilic bacterium Alicyclobacillus acidocaldarius belongs to the subfamily E1 of family 9 glycoside hydrolases, many members of which have an N-terminal Ig-like domain followed by the catalytic domain. The Ig-like domain is not directly involved in either carbohydrate binding or biocatalysis; however, deletion of the Ig-domain promotes loss of enzymatic activity. We have investigated the functional role of the Ig-like domain using molecular dynamics simulations. Our simulations indicate that residues within the Ig-like domain are dynamically correlated with residues in the carbohydrate-binding pocket and with key catalytic residues of Cel9A. Free energy perturbation simulations indicate that the Ig-like domain stabilizes the catalytic domain and may be responsible for the enhanced thermostability of Cel9A.

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Pac1 endonuclease and Dhp1p 5'-->3' exonuclease are required for U3 snoRNA termination in Schizosaccharomyces pombe.

Publication Date: 2010 Aug 4 PMID: 20609363
Authors: Nabavi, S. - Nazar, R. N.
Journal: FEBS Lett

Maturation of some snoRNAs is dependent on RNase III-like endonuclease-mediated transcript cleavage, which serves as an entry for the nuclear exosome complex that trims the transcript at the 3'-end. Sequence deletions suggest this cleavage in the U3 snoRNA transcripts of Schizosaccharomyces pombe can induce transcript termination. Using mutational analyses, we demonstrate that the degree of cleavage correlates closely with both RNA maturation and transcript termination. We also show that the RNase III-like endonuclease, Pac1, and the nuclear 5'-exonuclease, Dhp1p, are essential for RNA production and transcript termination, supporting a "reversed torpedoes" model in which the endonuclease cut allows 5'- and 3'-exonuclease activities access to the transcript, leading simultaneously to transcript termination in one direction and RNA maturation in the other.

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Cytoplasmic polyadenylation element-like sequences are involved in dendritic targeting of BDNF mRNA in hippocampal neurons.

Publication Date: 2010 Aug 4 PMID: 20603120
Authors: Oe, S. - Yoneda, Y.
Journal: FEBS Lett

Several mRNAs are known to be targeted to dendrites in hippocampal neurons. In this study, we show that brain-derived neurotrophic factor (BDNF) mRNA has two distinct cis-acting dendritic targeting elements in the short 3' untranslated region (UTR): a constitutive element and an activity-dependent one. Moreover, deletion of serial cytoplasmic polyadenylation element (CPE)-like sequences in the short 3'UTR suppressed both constitutive and activity-dependent dendritic targeting. In addition to the interaction with cytoplasmic polyadenylation element binding protein-1 (CPEB-1), depolarization enhanced CPEB-1 recruitment to the activity-dependent targeting element. These results suggest that CPE-like sequences are involved in the activity-dependent as well as constitutive dendritic targeting of BDNF mRNA.

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A reverse genetics system of African horse sickness virus reveals existence of primary replication.

Publication Date: 2010 Aug 4 PMID: 20600010
Authors: Matsuo, E. - Celma, C. C. - Roy, P.
Journal: FEBS Lett

African horse sickness virus (AHSV), a member of the orbivirus genus of the family Reoviridae, is an insect-vectored pathogen of horses of concern to the equine industry. Studies on AHSV replication and pathogenesis have been hampered by the lack of reverse genetics allowing targeted mutation of viral genomes. We demonstrate that AHSV single-stranded RNA synthesized in vitro (core transcripts) is infectious and that there are distinct primary and secondary stages of the replication cycle. Transfection with a mixture of core transcripts from two different serotypes or a mixture of core transcripts and a T7 derived transcript resulted in the recovery of reassortant viruses. Recovery of infectious ASHV from nucleic acid will benefit investigation of the virus and the generation of attenuated vaccines.

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Simulated microgravity promotes nitric oxide-supported angiogenesis via the iNOS-cGMP-PKG pathway in macrovascular endothelial cells.

Publication Date: 2010 Aug 4 PMID: 20600009
Authors: Siamwala, J. H. - Majumder, S. - Tamilarasan, K. P. - Muley, A. - Reddy, S. H. - Kolluru, G. K. - Sinha, S. - Chatterjee, S.
Journal: FEBS Lett

Angiogenesis is a physiological process involving the growth of blood vessel in response to specific stimuli. The present study shows that limited microgravity treatments induce angiogenesis by activating macrovascular endothelial cells. Inhibition of nitric oxide production using pharmacological inhibitors and inducible nitric oxide synthase (iNOS) small interfering ribo nucleic acid (siRNA) abrogated microgravity induced nitric oxide production in macrovascular cells. The study further delineates that iNOS acts as a molecular switch for the heterogeneous effects of microgravity on macrovascular, endocardial and microvascular endothelial cells. Further dissection of nitric oxide downstream signaling confirms that simulated microgravity induces angiogenesis via the cyclic guanosine monophosphate (cGMP)-PKG dependent pathway.

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MEK inhibitors suppress beta-amyloid production by altering the level of a beta-C-terminal fragment of amyloid precursor protein in neuronal cells.

Publication Date: 2010 Aug 4 PMID: 20600008
Authors: Araki, W. - Kametani, F. - Oda, A. - Tamaoka, A.
Journal: FEBS Lett

Beta-amyloid peptide (Abeta) is generated via sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-secretases. Cell-based screening experiments disclosed that the MEK (MAP kinase kinase) inhibitors, U0126 and PD184352, suppress Abeta secretion from human neuronal SH-SY5Y cells expressing Swedish mutant APP. These inhibitors did not affect the cellular levels of APP but significantly reduced those of the APP beta-C-terminal fragment (beta-CTF). Additionally, beta-CTF levels were markedly reduced by these inhibitors in cells expressing the fragment in a gamma-secretase-independent and proteasome-dependent manner. Our results suggest that MEK inhibitors reduce Abeta generation via secretase-independent alteration of beta-CTF levels.

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Mitochondrial respiration defects modulate differentiation but not proliferation of hematopoietic stem and progenitor cells.

Publication Date: 2010 Aug 4 PMID: 20600007
Authors: Inoue, S. - Noda, S. - Kashima, K. - Nakada, K. - Hayashi, J. - Miyoshi, H.
Journal: FEBS Lett

Mitochondrial energy production is involved in various cellular processes. Here we show that ATP content is significantly increased in lineage-restricted progenitor cells compared with hematopoietic stem and progenitor cells (HSPCs) or more differentiated cells. Transplantation analysis using a mouse model of mitochondrial disease revealed that mitochondrial respiration defects resulted in a significant decrease in the total number and repopulating activity of bone marrow cells, although the number of HSPCs increased. The proliferative activity of HSPCs and lineage-restricted progenitor cells was not impaired by reduction of ATP content and there seems to be no associated increase in reactive oxygen species levels and apoptosis. Our findings indicate that mitochondrial respiration defects modulate HSPC commitment/differentiation into lineage-restricted progenitor cells.

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Brown vs white adipocytes: the PPARgamma coregulator story.

Publication Date: 2010 Aug 4 PMID: 20600006
Authors: Koppen, A. - Kalkhoven, E.
Journal: FEBS Lett

The development of adipose tissue is a process which involves the concerted cooperation of numerous transcription factors together with their coactivators and corepressors. The peroxisome proliferator-activated receptor gamma (PPARgamma) is considered to be one of the master regulators of adipocyte differentiation. The presence of two functionally distinct types of adipose tissue, white and brown (WAT and BAT), requires an even more complex regulation of adipose tissue development. In this review we will focus on the role of PPARgamma coregulators in adipogenesis and especially on the role of PPARgamma coregulators in white and brown adipose tissue. Specificity in coregulator function in WAT and BAT may form an additional level of regulation of adipose tissue development.

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Loss of Trx-2 enhances oxidative stress-dependent phenotypes in Drosophila.

Publication Date: 2010 Aug 4 PMID: 20600005
Authors: Tsuda, M. - Ootaka, R. - Ohkura, C. - Kishita, Y. - Seong, K. H. - Matsuo, T. - Aigaki, T.
Journal: FEBS Lett

Overexpression of thioredoxin (TRX) confers oxidative stress resistance and extends lifespan in mammals and insects. However, less is known about phenotypes associated with loss of TRX. We investigated loss-of-function phenotypes of Trx-2 in Drosophila, and found that the mutant flies are hyper-susceptible to paraquat, a free radical generator, but not to hydrogen peroxide. They contain a high amount of protein carbonyl, which dramatically increases with age. Trx-2 mutants express high levels of anti-oxidant genes, such as superoxide dismutase, catalase, and glutathione synthetase. This is the first demonstration of biochemical and physiological consequences caused by loss of Trx-2 in Drosophila.

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Transcriptional suppression of breast cancer resistance protein (BCRP) by wild-type p53 through the NF-kappaB pathway in MCF-7 cells.

Publication Date: 2010 Aug 4 PMID: 20600004
Authors: Wang, X. - Wu, X. - Wang, C. - Zhang, W. - Ouyang, Y. - Yu, Y. - He, Z.
Journal: FEBS Lett

Breast cancer resistance protein (BCRP) has been shown to confer multidrug resistance, but the mechanisms of its regulation are poorly understood. Here, we investigate the effects of wild-type and mutant p53, and nuclear factor kappa-B (NF-kappaB) (p50) on BCRP promoter activity in MCF-7 cells. Our results demonstrated that wild-type p53 markedly suppressed BCRP activity and enhanced the chemosensitivity of cells to mitoxantrone, whereas mutant p53 had little inhibitory effect. After inhibition of NF-kappaB, similar results were obtained. Following knockdown of endogenous p53, BCRP and p50 expressions were increased, and the chemosensitivity of the cells to mitoxantrone was decreased. We conclude that wild-type p53 acts as a negative regulator of BCRP gene transcription.

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When the caps fall off: responses to telomere uncapping in yeast.

Publication Date: 2010 Sep 10 PMID: 20600003
Authors: Wellinger, R. J.
Journal: FEBS Lett

Telomeres protect the ends of linear chromosomes from activities that cause sequence losses or challenge chromosome integrity. Furthermore, these ends must be hidden from detection by the DNA damage recognition and response pathways. In particular, they must not fuse with each other. These fundamental and very first functions attributed to telomeres are also summarized with the term 'chromosome capping'. However, telomeres can become uncapped and the foremost cellular responses to such events aim to restore genome stability in the most conservative fashion possible. I will provide an outline of cellular responses to uncapping in budding yeast and briefly discuss the reverse, namely avoidance mechanisms that prevent telomere formation at inappropriate places.

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Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice.

Publication Date: 2010 Aug 4 PMID: 20600002
Authors: Li, B. - Wanka, L. - Blanchard, J. - Liu, F. - Chohan, M. O. - Iqbal, K. - Grundke-Iqbal, I.
Journal: FEBS Lett

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

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Heparin binding domain in vitronectin is required for oligomerization and thus enhances integrin mediated cell adhesion and spreading.

Publication Date: 2010 Aug 4 PMID: 20600001
Authors: Chillakuri, C. R. - Jones, C. - Mardon, H. J.
Journal: FEBS Lett

Vitronectin is a multi-functional protein found predominantly as a monomer in blood and as an oligomer in the extracellular matrix. We have dissected the minimal regions of vitronectin protein needed for effective integrin dependent cell adhesion and spreading. A fragment of vitronectin containing the RGD integrin binding site showed similar binding affinity as that of full vitronectin protein to purified integrin alphavbeta3 but had diminished cell adhesion and spreading function in vivo. We demonstrate that the oligomeric state of the protein is responsible for this effect. We provide compelling evidence for the involvement of the heparin binding domain of vitronectin in the oligomerization process and show that such oligomerization reinforces the activity of vitronectin in cell adhesion and spreading.

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Abi1/Hssh3bp1 pY213 links Abl kinase signaling to p85 regulatory subunit of PI-3 kinase in regulation of macropinocytosis in LNCaP cells.

Publication Date: 2010 Aug 4 PMID: 20598684
Authors: Dubielecka, P. M. - Machida, K. - Xiong, X. - Hossain, S. - Ogiue-Ikeda, M. - Carrera, A. C. - Mayer, B. J. - Kotula, L.
Journal: FEBS Lett

Macropinocytosis is regulated by Abl kinase via an unknown mechanism. We previously demonstrated that Abl kinase activity is, itself, regulated by Abi1 subsequent to Abl kinase phosphorylation of Abi1 tyrosine 213 (pY213) [1]. Here we show that blocking phosphorylation of Y213 abrogated the ability of Abl to regulate macropinocytosis, implicating Abi1 pY213 as a key regulator of macropinocytosis. Results from screening the human SH2 domain library and mapping the interaction site between Abi1 and the p85 regulatory domain of PI-3 kinase, coupled with data from cells transfected with loss-of-function p85 mutants, support the hypothesis that macropinocytosis is regulated by interactions between Abi1 pY213 and the C-terminal SH2 domain of p85-thereby linking Abl kinase signaling to p85-dependent regulation of macropinocytosis.

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A newly identified Pirh2 substrate SCYL1-BP1 can bind to MDM2 and accelerate MDM2 self-ubiquitination.

Publication Date: 2010 Aug 4 PMID: 20598683
Authors: Yan, J. - Zhang, D. - Di, Y. - Shi, H. - Rao, H. - Huo, K.
Journal: FEBS Lett

The SCY1-like 1 binding protein 1 (SCYL1-BP1) protein was identified as an interacting partner of E3 ligase p53-induced RING H2 protein (Pirh2) and mouse double minute gene number 2 (MDM2) by yeast two-hybrid screening. Further investigation suggested there are two interactions involved in different mechanisms. SCYL1-BP1 can be ubiquitinated and degraded by Pirh2 but not by MDM2, which suggests that SCYL1-BP1 can be regulated by Pirh2. On the other hand, while SCYL1-BP1 binds to ubiquitin E3 ligase MDM2, it promotes MDM2 self-ubiquitination and results in a reduction of MDM2 protein level.

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Syndecan- and integrin-binding peptides synergistically accelerate cell adhesion.

Publication Date: 2010 Aug 4 PMID: 20598296
Authors: Hozumi, K. - Kobayashi, K. - Katagiri, F. - Kikkawa, Y. - Kadoya, Y. - Nomizu, M.
Journal: FEBS Lett

Integrins and syndecans mediate cell adhesion to extracellular matrix and their synergistic cooperation is implicated in cell adhesion processes. We previously identified two active peptides, AG73 and EF1, from the laminin alpha1 chain LG4 module, that promote cell attachment through syndecan- and alpha2beta1 integrin-binding, respectively. Here, we examined time-dependent cell attachment on the mixed peptides AG73/EF1. The AG73/EF1 promoted stronger and more rapid cell attachment, spreading, FAK phosphorylation that reached a maximum at 20 min than that on AG73 (40 min) or EF1 (90 min) supplied singly. Thus, the syndecan- and alpha2beta1 integrin-binding peptides synergistically affect cells and accelerate cell adhesion.

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Solution structure of the N-terminal domain of the archaeal D-family DNA polymerase small subunit reveals evolutionary relationship to eukaryotic B-family polymerases.

Publication Date: 2010 Aug 4 PMID: 20598295
Authors: Yamasaki, K. - Urushibata, Y. - Yamasaki, T. - Arisaka, F. - Matsui, I.
Journal: FEBS Lett

Archaea-specific D-family DNA polymerase forms a heterotetramer consisting of two large polymerase subunits and two small exonuclease subunits. We analyzed the structure of the N-terminal 200 amino-acid regulatory region of the small subunit by NMR and revealed that the N-terminal approximately 70 amino-acid region is folded. The structure consists of a four-alpha-helix bundle including a short parallel beta-sheet, which is similar to the N-terminal regions of the B subunits of human DNA polymerases alpha and epsilon, establishing evolutionary relationships among these archaeal and eukaryotic polymerases. We observed monomer-dimer equilibrium of this domain, which may be related to holoenzyme architecture and/or functional regulation.

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Kinetic and thermodynamic properties of two barley thioredoxin h isozymes, HvTrxh1 and HvTrxh2.

Publication Date: 2010 Aug 4 PMID: 20594550
Authors: Maeda, K. - Hagglund, P. - Bjornberg, O. - Winther, J. R. - Svensson, B.
Journal: FEBS Lett

Barley thioredoxin h isozymes 1 (HvTrxh1) and barley thioredoxin h isozymes 2 (HvTrxh2) show distinct spatiotemporal distribution in germinating seeds. Using a novel approach involving measurement of bidirectional electron transfer rates between Escherichia coli thioredoxin, which exhibits redox-dependent fluorescence, and the barley isozymes, reaction kinetics and thermodynamic properties were readily determined. The reaction constants were approximately 60% higher for HvTrxh1 than HvTrxh2, while their redox potentials were very similar. The primary nucleophile, CysN, of the active site Trp-CysN-Gly-Pro-CysC motif has an apparent pKa of 7.6 in both isozymes, as found by iodoacetamide titration, but showed approximately 70% higher reactivity in HvTrxh1, suggesting significant functional difference between the isozymes.

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S100 proteins interact with the N-terminal domain of MDM2.

Publication Date: 2010 Aug 4 PMID: 20591429
Authors: van Dieck, J. - Lum, J. K. - Teufel, D. P. - Fersht, A. R.
Journal: FEBS Lett

S100 proteins interact with the transactivation domain and the C-terminus of p53. Further, S100B has been shown to interact with MDM2, a central negative regulator of p53. Here, we show that S100B bound directly to the folded N-terminal domain of MDM2 (residues 2-125) by size exclusion chromatography and surface plasmon resonance experiments. This interaction with MDM2 (2-125) is a general feature of S100 proteins; S100A1, S100A2, S100A4 and S100A6 also interact with MDM2 (2-125). These interactions with S100 proteins do not result in a ternary complex with MDM2 (2-125) and p53. Instead, we observe the ability of a subset of S100 proteins to disrupt the extent of MDM2-mediated p53 ubiquitylation in vitro.

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The human xenobiotic-metabolizing enzyme arylamine N-acetyltransferase 1 (NAT1) is irreversibly inhibited by inorganic (Hg2+) and organic mercury (CH3Hg+): mechanism and kinetics.

Publication Date: 2010 Aug 4 PMID: 20591428
Authors: Ragunathan, N. - Busi, F. - Pluvinage, B. - Sanfins, E. - Dupret, J. M. - Rodrigues-Lima, F. - Dairou, J.
Journal: FEBS Lett

Human arylamine N-acetyltransferase 1 (NAT1) is a xenobiotic-metabolizing enzyme that biotransforms aromatic amine chemicals. We show here that biologically-relevant concentrations of inorganic (Hg2+) and organic (CH3Hg+) mercury inhibit the biotransformation functions of NAT1. Both compounds react irreversibly with the active-site cysteine of NAT1 (half-maximal inhibitory concentration (IC50)=250 nM and kinact=1.4x10(4) M(-1) s(-1) for Hg2+ and IC50=1.4 microM and kinact=2x10(2) M(-1) s(-1) for CH3Hg+). Exposure of lung epithelial cells led to the inhibition of cellular NAT1 (IC50=3 and 20 microM for Hg2+ and CH3Hg+, respectively). Our data suggest that exposure to mercury may affect the biotransformation of aromatic amines by NAT1.

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Multiple roles of ATM in monitoring and maintaining DNA integrity.

Publication Date: 2010 Sep 10 PMID: 20580718
Authors: Derheimer, F. A. - Kastan, M. B.
Journal: FEBS Lett

The ability of our cells to maintain genomic integrity is fundamental for protection from cancer development. Central to this process is the ability of cells to recognize and repair DNA damage and progress through the cell cycle in a regulated and orderly manner. In addition, protection of chromosome ends through the proper assembly of telomeres prevents loss of genetic information and aberrant chromosome fusions. Cells derived from patients with ataxia-telangiectasia (A-T) show defects in cell cycle regulation, abnormal responses to DNA breakage, and chromosomal end-to-end fusions. The identification and characterization of the ATM (ataxia-telangiectasia, mutated) gene product has provided an essential tool for researchers in elucidating cellular mechanisms involved in cell cycle control, DNA repair, and chromosomal stability.

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Regulation of homologous recombination at telomeres in budding yeast.

Publication Date: 2010 Sep 10 PMID: 20580716
Authors: Eckert-Boulet, N. - Lisby, M.
Journal: FEBS Lett

Homologous recombination is suppressed at normal length telomere sequences. In contrast, telomere recombination is allowed when telomeres erode in the absence of telomerase activity or as a consequence of nucleolytic degradation or incomplete replication. Here, we review the mechanisms that contribute to regulating mitotic homologous recombination at telomeres and the role of these mechanisms in signalling short telomeres in the budding yeast Saccharomyces cerevisiae.

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Comparative biology of telomeres: where plants stand.

Publication Date: 2010 Sep 10 PMID: 20580356
Authors: Watson, J. M. - Riha, K.
Journal: FEBS Lett

Telomeres are essential structures at the ends of eukaryotic chromosomes. Work on their structure and function began almost 70 years ago in plants and flies, continued through the Nobel Prize winning work on yeast and ciliates, and goes on today in many model and non-model organisms. The basic molecular mechanisms of telomeres are highly conserved throughout evolution, and our current understanding of how telomeres function is a conglomeration of insights gained from many different species. This review will compare the current knowledge of telomeres in plants with other organisms, with special focus on the functional length of telomeric DNA, the search for TRF homologs, the family of POT1 proteins, and the recent discovery of members of the CST complex.

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A predicted S-type pyocin shows a bactericidal activity against clinical Pseudomonas aeruginosa isolates through membrane damage.

Publication Date: 2010 Aug 4 PMID: 20580355
Authors: Ling, H. - Saeidi, N. - Rasouliha, B. H. - Chang, M. W.
Journal: FEBS Lett

The nucleic acid sequence at the positions 1067817-1066321 of Pseudomonas aeruginosa PAO1 genome was predicted to encode a novel S-type pyocin, designated S5, based on the genome sequence. However, its antimicrobial spectrum, activity and mechanism have not been investigated. Herein, we report that pyocin S5 has an antimicrobial activity against seven clinical P. aeruginosa isolates (DWW3, InA, InB, In3, In4, In7, and In8). Among them, DWW3 is most sensitive with a minimum inhibitory concentration of 12.6 microg/ml and a killing percentage of 95.7 at 225 microg/ml. Further, we demonstrated that the antimicrobial mechanism of pyocin S5 is membrane damage, evidenced by the leakage of intracellular materials, the increase of membrane permeability, and cell surface disruption.

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The amyloid fibrils of the constant domain of immunoglobulin light chain.

Publication Date: 2010 Aug 4 PMID: 20580354
Authors: Yamamoto, K. - Yagi, H. - Lee, Y. H. - Kardos, J. - Hagihara, Y. - Naiki, H. - Goto, Y.
Journal: FEBS Lett

Light chain-associated (AL) amyloidosis is characterized by dominant fibril deposition of the variable domain (VL) of an immunoglobulin light chain, and thus its constant domain (CL) has been considered not to be amyloidogenic. We examined the in vitro fibril formation of the isolated CL in comparison with beta2-microglobulin (beta2-m), an immunoglobulin domain-like amyloidogenic protein responsible for dialysis-related amyloidosis. Two methods useful for beta2-m at neutral pH also induced amyloid fibrils of CL, which were monitored by thioflavin-T binding and electron microscopy (EM). These results suggest that CL plays an important role, more than previously assumed, in the development of AL-amyloidosis.

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Focus on...the role of PPARgamma in adipogenesis.

Publication Date: 2010 Aug 4 PMID: 20579984
Authors: Just, W.
Journal: FEBS Lett

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Defending the end zone: studying the players involved in protecting chromosome ends.

Publication Date: 2010 Sep 10 PMID: 20579983
Authors: Chan, S. S. - Chang, S.
Journal: FEBS Lett

The linear nature of eukaryotic chromosomes leaves natural DNA ends susceptible to triggering DNA damage responses. Telomeres are specialized nucleoprotein structures that comprise the "end zone" of chromosomes. Besides having specialized sequences and structures, there are six resident proteins at telomeres that play prominent roles in protecting chromosome ends. In this review, we discuss this team of proteins, termed shelterin, and how it is involved in regulating DNA damage signaling, repair and replication at telomeres.

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OGFOD1, a member of the 2-oxoglutarate and iron dependent dioxygenase family, functions in ischemic signaling.

Publication Date: 2010 Aug 4 PMID: 20579638
Authors: Saito, K. - Adachi, N. - Koyama, H. - Matsushita, M.
Journal: FEBS Lett

The 2-oxoglutarate and iron dependent dioxygenase family are crucial for cellular adaptation to changes in oxygen concentration. We found that cells with OGFOD1 gene silencing in this family showed resistance to cell death under ischemia, and cDNA microarray analysis of OGFOD1 knockout human cells revealed downregulation of ATPAF1. Although reintroduction of the OGFOD1 wild-type gene to OGFOD1 KO cells restored ATPAF1 mRNA levels, the catalytically inactive OGFOD1 mutants did not. Furthermore, introduction of ATPAF1 gene to OGFOD1 KO cells induced ischemic cell death. Thus, OGFOD1 plays an important role in ischemic cell survival and an OGFOD1 iron binding residue is required for ATPAF1 gene expression.

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PPARgamma in adipocyte differentiation and metabolism--novel insights from genome-wide studies.

Publication Date: 2010 Aug 4 PMID: 20542036
Authors: Siersbaek, R. - Nielsen, R. - Mandrup, S.
Journal: FEBS Lett

Adipocyte differentiation is controlled by a tightly regulated transcriptional cascade in which PPARgamma and members of the C/EBP family are key players. Here we review the roles of PPARgamma and C/EBPs in adipocyte differentiation with emphasis on the recently published genome-wide binding profiles for PPARgamma and C/EBPalpha. Interestingly, these analyses show that PPARgamma and C/EBPalpha binding sites are associated with most genes that are induced during adipogenesis suggesting direct activation of many more adipocyte genes than previously anticipated. Furthermore, an extensive overlap between the C/EBPalpha and PPARgamma cistromes indicate a hitherto unrecognized direct crosstalk between these transcription factors. As more genome-wide data emerge in the future, this crosstalk will likely be found to include several other adipogenic transcription factors.

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Evolution of MHC class I genes in two ancient fish, paddlefish (Polyodon spathula) and Chinese sturgeon (Acipenser sinensis).

Publication Date: 2010 Aug 4 PMID: 20542035
Authors: Wang, D. - Zhong, L. - Wei, Q. - Gan, X. - He, S.
Journal: FEBS Lett

Here we present the first isolation of major histocompatibility complex (MHC) class I genes from two ancient fish, paddlefish (Polyodon spathula) and Chinese sturgeon (Acipenser sinensis). Seventeen sequences obtained showed high polymorphism and positive natural selection with dN/dS>1. Evolutionary relationships revealed that sequences from paddlefish and Chinese sturgeon distinguished from other vertebrate class I and had an intermingling of alleles, which indicates that Acipenseriformes have a common ancestral gene of class I and a trans-species polymorphism across Acipenseriformes. We also found clear evidence of recombination among class I genes of paddlefish and Chinese sturgeon.

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Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers.

Publication Date: 2010 Sep 10 PMID: 20542034
Authors: Henson, J. D. - Reddel, R. R.
Journal: FEBS Lett

Alternative Lengthening of Telomeres (ALT) activity can be deduced from the presence of telomere length maintenance in the absence of telomerase activity. More convenient assays for ALT utilize phenotypic markers of ALT activity, but only a few of these assays are potentially definitive. Here we assess each of the current ALT assays and their implications for understanding the ALT mechanism. We also review the clinical situations where availability of an ALT activity assay would be advantageous. The prevalence of ALT ranges from 25% to 60% in sarcomas and 5% to 15% in carcinomas. Patients with many of these types of ALT[+] tumors have a poor prognosis.

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Dyskeratosis congenita.

Publication Date: 2010 Sep 10 PMID: 20493861
Authors: Bessler, M. - Wilson, D. B. - Mason, P. J.
Journal: FEBS Lett

Dyskeratosis congenita (DC) was originally defined as a rare inherited bone marrow failure (BMF) syndrome associated with distinct mucocutaneous features. Today DC is defined by its pathogenetic mechanism and mutations in components of the telomere maintenance machinery resulting in excessively short telomeres in highly proliferating tissues. With this new definition the disease spectrum has broadened and ranges from intrauterine growth retardation, cerebellar hypoplasia, and death in early childhood to asymptomatic mutation carriers whose descendants are predisposed to malignancy, BMF, or pulmonary disease. The degree of telomere dysfunction is the major determinant of disease onset and manifestations.

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Focus on histone variant H2AX: to be or not to be.

Publication Date: 2010 Sep 10 PMID: 20493860
Authors: Yuan, J. - Adamski, R. - Chen, J.
Journal: FEBS Lett

Phosphorylation of histone variant H2AX at serine 139, named gammaH2AX, has been widely used as a sensitive marker for DNA double-strand breaks (DSBs). gammaH2AX is required for the accumulation of many DNA damage response (DDR) proteins at DSBs. Thus it is believed to be the principal signaling protein involved in DDR and to play an important role in DNA repair. However, only mild defects in DNA damage signaling and DNA repair were observed in H2AX-deficient cells and animals. Such findings prompted us and others to explore H2AX-independent mechanisms in DNA damage response. Here, we will review recent advances in our understanding of H2AX-dependent and independent DNA damage signaling and repair pathways in mammalian cells.

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Pot1 and telomere maintenance.

Publication Date: 2010 Sep 10 PMID: 20493859
Authors: Baumann, P. - Price, C.
Journal: FEBS Lett

Proteins that specifically bind the single-stranded overhang at the ends of telomeres have been identified in a wide range of eukaryotes and play pivotal roles in chromosome end protection and telomere length regulation. Here we summarize recent findings regarding the functions of POT1 proteins in vertebrates and discuss the functional evolution of POT1 proteins following gene duplication in protozoa, plants, nematodes and mice.

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Telomeres and telomerase in normal and cancer stem cells.

Publication Date: 2010 Sep 10 PMID: 20493857
Authors: Shay, J. W. - Wright, W. E.
Journal: FEBS Lett

Differences between normal adult tissue stem cells and cancer stem/initiating cells remain poorly defined. For example, it is controversial if cancer stem cells can become fully quiescent, require a stem cell niche, are better at repairing DNA damage than the bulk of the cancer cells, and if and how they regulate symmetric versus asymmetric cell divisions. This minireview will not only provide our personal views to address some of these outstanding questions, but also present evidence that an understanding of telomere dynamics and telomerase activity in normal and cancer stem cells may provide additional insights into how tumors are initiated, and how they should be monitored and treated.

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Metabolism of postsynaptic recombination intermediates.

Publication Date: 2010 Sep 10 PMID: 20493853
Authors: Adelman, C. A. - Boulton, S. J.
Journal: FEBS Lett

DNA double strand breaks and blocked or collapsed DNA replication forks are potentially genotoxic lesions that can result in deletions, aneuploidy or cell death. Homologous recombination (HR) is an essential process employed during repair of these forms of damage. HR allows for accurate restoration of the damaged DNA through use of a homologous template for repair. Although inroads have been made towards understanding the mechanisms of HR, ambiguity still surrounds aspects of the process. Until recently, relatively little was known concerning metabolism of postsynaptic RAD51 filaments or how synthesis dependent strand annealing intermediates are processed. This review discusses recent findings implicating RTEL1, HELQ and the Caenorhabditis elegans RAD51 paralog RFS-1 in post-strand exchange events during HR.

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An emerging role for bromodomain-containing proteins in chromatin regulation and transcriptional control of adipogenesis.

Publication Date: 2010 Aug 4 PMID: 20493850
Authors: Denis, G. V. - Nikolajczyk, B. S. - Schnitzler, G. R.
Journal: FEBS Lett

Transcriptional co-activators, co-repressors and chromatin remodeling machines are essential elements in the transcriptional programs directed by the master adipogenic transcription factor PPARgamma. Many of these components have orthologs in other organisms, where they play roles in development and pattern formation, suggesting new links between cell fate decision-making and adipogenesis. This review focuses on bromodomain-containing protein complexes recently shown to play a critical role in adipogenesis. Deeper understanding of these pathways is likely to have major impact on treatment of obesity-associated diseases, including metabolic syndrome, cardiovascular disease and Type 2 diabetes. The research effort is urgent because the obesity epidemic is serious; the medical community is ill prepared to cope with the anticipated excess morbidity and mortality associated with diet-induced obesity.

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