Nature Cell Biology

DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery.

Publication Date: 2010 Mar PMID: 20190832
Authors: Ahmed, S. - Brickner, D. G. - Light, W. H. - Cajigas, I. - McDonough, M. - Froyshteter, A. B. - Volpe, T. - Brickner, J. H.
Journal: Nat Cell Biol

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Tipping the scale: muscle versus fat.

Publication Date: 2010 Mar PMID: 20190831
Authors: Rodeheffer, M. S.
Journal: Nat Cell Biol

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Research highlights.

Publication Date: 2010 Mar PMID: 20190830
Authors: Chenette, E. - Le Bot, N. - Rosenthal, C. K. - Swaminathan, S.
Journal: Nat Cell Biol

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p62, an autophagy hero or culprit?

Publication Date: 2010 Mar PMID: 20190829
Authors: Rusten, T. E. - Stenmark, H.
Journal: Nat Cell Biol

The p62 protein recognizes toxic cellular waste, which is then scavenged by a sequestration process known as self-eating or autophagy. Lack of autophagy leads to accumulation of p62, which is not good for liver cells, as it induces a cellular stress response that leads to disease.

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PTH battles TGF-beta in bone.

Publication Date: 2010 Mar PMID: 20190828
Authors: Atfi, A. - Baron, R.
Journal: Nat Cell Biol

Bone remodelling in vertebrates is coordinately regulated by the opposing effects of parathyroid hormone (PTH) and transforming growth factor-beta (TGF-beta). PTH couples the processes of bone resorption and formation by enforcing simultaneous internalization of TGF-beta type II receptor (TbetaRII) and PTH type 1 receptor (PTH1R), which attenuates both TGF-beta and PTH signalling in vivo.

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The peroxisomal protein importomer: a bunch of transients with expanding waistlines.

Publication Date: 2010 Mar PMID: 20190827
Authors: Mast, F. D. - Fagarasanu, A. - Rachubinski, R.
Journal: Nat Cell Biol

Peroxisomes can import large multimeric protein complexes and even 9-nm gold particles decorated with peroxisome-targeting signals. They achieve these feats of protein passage using a distinctive translocon whose highly dynamic aqueous pore can expand to accommodate the increasing girths of different peroxisome receptor-cargo complexes.

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New beginnings: getting the kick I needed.

Publication Date: 2010 Mar PMID: 20190826
Authors: Simons, K.
Journal: Nat Cell Biol

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Science without borders.

Publication Date: 2010 Mar PMID: 20190825
Authors:
Journal: Nat Cell Biol

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A deneddylase encoded by Epstein-Barr virus promotes viral DNA replication by regulating the activity of cullin-RING ligases.

Publication Date: 2010 Feb 28 PMID: 20190741
Authors: Gastaldello, S. - Hildebrand, S. - Faridani, O. - Callegari, S. - Palmkvist, M. - Di Guglielmo, C. - Masucci, M. G.
Journal: Nat Cell Biol

The large tegument proteins of herpesviruses encode conserved cysteine proteases of unknown function. Here we show that BPLF1, the Epstein-Barr-virus-encoded member of this protease family, is a deneddylase that regulates virus production by modulating the activity of cullin-RING ligases (CRLs). BPLF1 hydrolyses NEDD8 conjugates in vitro, acts as a deneddylase in vivo, binds to cullins and stabilizes CRL substrates. Expression of BPLF1 alone or in the context of the productive virus cycle induces accumulation of the licensing factor CDT1 and deregulates S-phase DNA synthesis. Inhibition of BPLF1 during the productive virus cycle prevents cellular DNA re-replication and inhibits virus replication. Viral DNA synthesis is restored by overexpression of CDT1. Homologues encoded by other herpesviruses share the deneddylase activity. Thus, these enzymes are likely to have a key function in the virus life cycle by inducing a replication-permissive S-phase-like cellular environment.

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Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia.

Publication Date: 2010 Feb 28 PMID: 20190740
Authors: Mavrakis, K. J. - Wolfe, A. L. - Oricchio, E. - Palomero, T. - de Keersmaecker, K. - McJunkin, K. - Zuber, J. - James, T. - Khan, A. A. - Leslie, C. S. - Parker, J. S. - Paddison, P. J. - Tam, W. - Ferrando, A. - Wendel, H. G.
Journal: Nat Cell Biol

MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the miR-17-92 cluster, containing six individual miRNAs, is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo. Clinical use of these findings hinges on isolating the oncogenic activity within the 17-92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1-induced T-cell acute lymphoblastic leukaemia (T-ALL) in vivo. In concord with the pathogenic importance of this interaction in T-ALL, we report a novel translocation that targets the 17-92 cluster and coincides with a second rearrangement that activates Notch1. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short hairpin RNA screen for genes whose knockdown can phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and include Bim (Bcl2L11), AMP-activated kinase (Prkaa1) and the phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clampdown on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukaemogenic miR-19.

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Myc-modulated miR-9 makes more metastases.

Publication Date: 2010 Mar PMID: 20173743
Authors: Khew-Goodall, Y. - Goodall, G. J.
Journal: Nat Cell Biol

The microRNA miR-9 is induced by Myc in breast cancer cells where it targets the major epithelial adherens junction protein, E-cadherin. This primes the cancer cells for epithelial-mesenchymal transition (EMT) and also stimulates angiogenesis in tumours.

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The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.

Publication Date: 2010 Mar PMID: 20173742
Authors: Komatsu, M. - Kurokawa, H. - Waguri, S. - Taguchi, K. - Kobayashi, A. - Ichimura, Y. - Sou, Y. S. - Ueno, I. - Sakamoto, A. - Tong, K. I. - Kim, M. - Nishito, Y. - Iemura, S. - Natsume, T. - Ueno, T. - Kominami, E. - Motohashi, H. - Tanaka, K. - Yamamoto, M.
Journal: Nat Cell Biol

Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.

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Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity.

Publication Date: 2010 Mar PMID: 20173741
Authors: Coolen, M. W. - Stirzaker, C. - Song, J. Z. - Statham, A. L. - Kassir, Z. - Moreno, C. S. - Young, A. N. - Varma, V. - Speed, T. P. - Cowley, M. - Lacaze, P. - Kaplan, W. - Robinson, M. D. - Clark, S. J.
Journal: Nat Cell Biol

Silencing of individual genes can occur by genetic and epigenetic processes during carcinogenesis, but the underlying mechanisms remain unclear. By creating an integrated prostate cancer epigenome map using tiling arrays, we show that contiguous regions of gene suppression commonly occur through long-range epigenetic silencing (LRES). We identified 47 LRES regions in prostate cancer, typically spanning about 2 Mb and harbouring approximately 12 genes, with a prevalence of tumour suppressor and miRNA genes. Our data reveal that LRES is associated with regional histone deacetylation combined with subdomains of different epigenetic remodelling patterns, which include re-enforcement, gain or exchange of repressive histone, and DNA methylation marks. The transcriptional and epigenetic state of genes in normal prostate epithelial and human embryonic stem cells can play a critical part in defining the mode of cancer-associated epigenetic remodelling. We propose that consolidation or effective reduction of the cancer genome commonly occurs in domains through a combination of LRES and LOH or genomic deletion, resulting in reduced transcriptional plasticity within these regions.

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miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis.

Publication Date: 2010 Mar PMID: 20173740
Authors: Ma, L. - Young, J. - Prabhala, H. - Pan, E. - Mestdagh, P. - Muth, D. - Teruya-Feldstein, J. - Reinhardt, F. - Onder, T. T. - Valastyan, S. - Westermann, F. - Speleman, F. - Vandesompele, J. - Weinberg, R. A.
Journal: Nat Cell Biol

MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of beta-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.

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The peroxisomal importomer constitutes a large and highly dynamic pore.

Publication Date: 2010 Mar PMID: 20154681
Authors: Meinecke, M. - Cizmowski, C. - Schliebs, W. - Kruger, V. - Beck, S. - Wagner, R. - Erdmann, R.
Journal: Nat Cell Biol

The peroxisomal protein import machinery differs fundamentally from known translocons (endoplasmic reticulum, mitochondria, chloroplasts, bacteria) as it allows membrane passage of folded, even oligomerized proteins. However, the mechanistic principles of protein translocation across the peroxisomal membrane remain unknown. There are various models that consider membrane invagination events, vesicle fusion or the existence of large import pores. Current data show that a proteinaceous peroxisomal importomer enables docking of the cytosolic cargo-loaded receptors, cargo translocation and receptor recycling. Remarkably, the cycling import receptor Pex5p changes its topology from a soluble cytosolic form to an integral membrane-bound form. According to the transient pore hypothesis, the membrane-bound receptor is proposed to form the core component of the peroxisomal import pore. Here, we demonstrate that the membrane-associated import receptor Pex5p together with its docking partner Pex14p forms a gated ion-conducting channel which can be opened to a diameter of about 9 nm by the cytosolic receptor-cargo complex. The newly identified pore shows striking dynamics, as expected for an import machinery translocating proteins of variable sizes.

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TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI.

Publication Date: 2010 Mar PMID: 20154680
Authors: Chaudhury, A. - Hussey, G. S. - Ray, P. S. - Jin, G. - Fox, P. L. - Howe, P. H.
Journal: Nat Cell Biol

Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, the identification of TGF-beta-inducible, EMT-specific genes has met with limited success. Here we identify a post-transcriptional pathway by which TGF-beta modulates the expression of EMT-specific proteins and of EMT itself. We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation. TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. Modulation of hnRNP E1 expression or its post-translational modification alters the TGF-beta-mediated reversal of translational silencing of the target transcripts and EMT. These results suggest the existence of a TGF-beta-inducible post-transcriptional regulon that controls EMT during the development and metastatic progression of tumours.

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Identification of the cell lineage at the origin of basal cell carcinoma.

Publication Date: 2010 Mar PMID: 20154679
Authors: Youssef, K. K. - Van Keymeulen, A. - Lapouge, G. - Beck, B. - Michaux, C. - Achouri, Y. - Sotiropoulou, P. A. - Blanpain, C.
Journal: Nat Cell Biol

For most types of cancers, the cell at the origin of tumour initiation is still unknown. Here, we used mouse genetics to identify cells at the origin of basal cell carcinoma (BCC), which is one of the most frequently occurring types of cancer in humans, and can result from the activation of the Hedgehog signalling pathway. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2), we activated Hedgehog signalling in different cellular compartments of the skin epidermis and determined in which compartments Hedgehog activation induces BCC formation. Activation of SmoM2 in hair follicle bulge stem cells and their transient amplifying progenies did not induce cancer formation, demonstrating that BCC does not originate from bulge stem cells, as previously thought. Using clonal analysis, we found that BCC arises from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. Our studies uncover the cells at the origin of BCC in mice and demonstrate that expression of differentiation markers in tumour cells is not necessarily predictive of the cancer initiating cells.

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TGF-beta type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling.

Publication Date: 2010 Mar PMID: 20139972
Authors: Qiu, T. - Wu, X. - Zhang, F. - Clemens, T. L. - Wan, M. - Cao, X.
Journal: Nat Cell Biol

Parathyroid hormone (PTH) regulates calcium homeostasis and bone metabolism by activating PTH type I receptor (PTH1R). Here we show that transforming growth factor (TGF)-beta type II receptor (TbetaRII) forms an endocytic complex with PTH1R in response to PTH and regulates signalling by PTH and TGF-beta. TbetaRII directly phosphorylates the PTH1R cytoplasmic domain, which modulates PTH-induced endocytosis of the PTH1R-TbetaRII complex. Deletion of TbetaRII in osteoblasts increases the cell-surface expression of PTH1R and augments PTH signalling. Conditional knockout of TbetaRII in osteoblasts in mice results in a high bone mass with increased trabecular bone and decreased cortical bone, similar to the bone phenotype in mice expressing a constitutively active PTH1R. Disruption of PTH signalling by injection of PTH(7-34) or ablation of PTH1R rescues the bone phenotype of TbetaRII knockout mice. These studies reveal a previously unrecognized function for TbetaRII and a mechanism for integration of PTH and local growth factor at the membrane receptor level.

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Histone H3 Thr 45 phosphorylation is a replication-associated post-translational modification in S. cerevisiae.

Publication Date: 2010 Mar PMID: 20139971
Authors: Baker, S. P. - Phillips, J. - Anderson, S. - Qiu, Q. - Shabanowitz, J. - Smith, M. M. - Yates, J. R. 3rd - Hunt, D. F. - Grant, P. A.
Journal: Nat Cell Biol

Post-translational histone modifications are crucial for the regulation of numerous DNA-templated processes, and are thought to mediate both alteration of chromatin dynamics and recruitment of effector proteins to specific regions of the genome. In particular, histone Ser/Thr phosphorylation regulates multiple nuclear functions in the budding yeast Saccharomyces cerevisiae, including transcription, DNA damage repair, mitosis, apoptosis and sporulation. Although modifications to chromatin during replication remain poorly understood, a number of recent studies have described acetylation of the histone H3 N-terminal alpha-helix (alphaN helix) at Lys 56 as a modification that is important for maintenance of genomic integrity during DNA replication and repair. Here, we report phosphorylation of H3 Thr 45 (H3-T45), a histone modification also located within the H3 alphaN helix in S. cerevisiae. Thr 45 phosphorylation peaks during DNA replication, and is mediated by the S phase kinase Cdc7-Dbf4 as part of a multiprotein complex identified in this study. Furthermore, loss of phosphorylated H3-T45 causes phenotypes consistent with replicative defects, and prolonged replication stress results in H3-T45 phosphorylation accumulation over time. Notably, the phenotypes described here are independent of Lys 56 acetylation status, and combinatorial mutations to both Thr 45 and Lys 56 of H3 cause synthetic growth defects. Together, these data identify and characterize H3-T45 phosphorylation as a replication-associated histone modification in budding yeast.

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Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development.

Publication Date: 2010 Mar PMID: 20118923
Authors: Mitchell, K. J. - Pannerec, A. - Cadot, B. - Parlakian, A. - Besson, V. - Gomes, E. R. - Marazzi, G. - Sassoon, D. A.
Journal: Nat Cell Biol

Satellite cells are resident myogenic progenitors in postnatal skeletal muscle involved in muscle postnatal growth and adult regenerative capacity. Here, we identify and describe a population of muscle-resident stem cells, which are located in the interstitium, that express the cell stress mediator PW1 but do not express other markers of muscle stem cells such as Pax7. PW1(+)/Pax7(-) interstitial cells (PICs) are myogenic in vitro and efficiently contribute to skeletal muscle regeneration in vivo as well as generating satellite cells and PICs. Whereas Pax7 mutant satellite cells show robust myogenic potential, Pax7 mutant PICs are unable to participate in myogenesis and accumulate during postnatal growth. Furthermore, we found that PICs are not derived from a satellite cell lineage. Taken together, our findings uncover a new and anatomically identifiable population of muscle progenitors and define a key role for Pax7 in a non-satellite cell population during postnatal muscle growth.

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Membrane contacts between endosomes and ER provide sites for PTP1B-epidermal growth factor receptor interaction.

Publication Date: 2010 Mar PMID: 20118922
Authors: Eden, E. R. - White, I. J. - Tsapara, A. - Futter, C. E.
Journal: Nat Cell Biol

The epidermal growth factor receptor (EGFR) is a critical determinator of cell fate. Signalling from this receptor tyrosine kinase is spatially regulated by progression through the endocytic pathway, governing receptor half-life and accessibility to signalling proteins and phosphatases. Endocytosis of EGFR is required for interaction with the protein tyrosine phosphatase PTP1B (ref. 1), which localizes to the cytoplasmic face of the endoplasmic reticulum (ER), raising the question of how PTP1B comes into contact with endosomal EGFR. We show that EGFR-PTP1B interaction occurs by means of direct membrane contacts between the perimeter membrane of multivesicular bodies (MVBs) and the ER. The population of EGFR interacting with PTP1B is the same population that undergo ESCRT-mediated (endosomal sorting complex required for transport) sorting within MVBs, and PTP1B activity promotes the sequestration of EGFR on to MVB internal vesicles. Membrane contacts between endosomes and the ER form in both the presence and absence of stimulation by EGF. Thus membrane contacts between endosomes and the ER may represent a global mechanism for direct interaction between proteins on these two organelles.

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Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex.

Publication Date: 2010 Mar PMID: 20118921
Authors: Ishitani, T. - Hirao, T. - Suzuki, M. - Isoda, M. - Ishitani, S. - Harigaya, K. - Kitagawa, M. - Matsumoto, K. - Itoh, M.
Journal: Nat Cell Biol

The Notch signalling pathway has a crucial function in determining cell fates in multiple tissues within metazoan organisms. On binding to ligands, the Notch receptor is cleaved proteolytically and releases its intracellular domain (NotchICD). The NotchICD enters the nucleus and acts cooperatively with other factors to stimulate the transcription of target genes. High levels of Notch-mediated transcriptional activation require the formation of a ternary complex consisting of NotchICD, CSL (CBF-1, suppressor of hairless, LAG-1) and a Mastermind family member. However, it is still not clear how the formation of the ternary complex is regulated. Here we show that Nemo-like kinase (NLK) negatively regulates Notch-dependent transcriptional activation by decreasing the formation of this ternary complex. Using a biochemical screen, we identified Notch as a new substrate of NLK. NLK-phosphorylated Notch1ICD is impaired in its ability to form a transcriptionally active ternary complex. Furthermore, knockdown of NLK leads to hyperactivation of Notch signalling and consequently decreases neurogenesis in zebrafish. Our results both define a new function for NLK and reveal a previously unidentified mode of regulation in the Notch signalling pathway.

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