Cell

SnapShot: F Box Proteins II.

Publication Date: 2009 Jun 26 PMID: 19563764
Authors: Skaar, J. R. - D'Angiolella, V. - Pagan, J. K. - Pagano, M.
Journal: Cell

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Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut.

Publication Date: 2009 Jun 26 PMID: 19563763
Authors: Jiang, H. - Patel, P. H. - Kohlmaier, A. - Grenley, M. O. - McEwen, D. G. - Edgar, B. A.
Journal: Cell

Cells in intestinal epithelia turn over rapidly due to damage from digestion and toxins produced by the enteric microbiota. Gut homeostasis is maintained by intestinal stem cells (ISCs) that divide to replenish the intestinal epithelium, but little is known about how ISC division and differentiation are coordinated with epithelial cell loss. We show here that when enterocytes (ECs) in the Drosophila midgut are subjected to apoptosis, enteric infection, or JNK-mediated stress signaling, they produce cytokines (Upd, Upd2, and Upd3) that activate Jak/Stat signaling in ISCs, promoting their rapid division. Upd/Jak/Stat activity also promotes progenitor cell differentiation, in part by stimulating Delta/Notch signaling, and is required for differentiation in both normal and regenerating midguts. Hence, cytokine-mediated feedback enables stem cells to replace spent progeny as they are lost, thereby establishing gut homeostasis.

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Pulsed forces timed by a ratchet-like mechanism drive directed tissue movement during dorsal closure.

Publication Date: 2009 Jun 26 PMID: 19563762
Authors: Solon, J. - Kaya-Copur, A. - Colombelli, J. - Brunner, D.
Journal: Cell

Dorsal closure is a tissue-modeling process in the developing Drosophila embryo during which an epidermal opening is closed. It begins with the appearance of a supracellular actin cable that surrounds the opening and provides a contractile force. Amnioserosa cells that fill the opening produce an additional critical force pulling on the surrounding epidermal tissue. We show that this force is not gradual but pulsed and occurs long before dorsal closure starts. Quantitative analysis, combined with laser cutting experiments and simulations, reveals that tension-based dynamics and cell coupling control the force pulses. These constitutively pull the surrounding epidermal tissue dorsally, but the displacement is initially transient. It is translated into dorsal-ward movement only with the help of the actin cable, which acts like a ratchet, counteracting ventral-ward epidermis relaxation after force pulses. Our work uncovers a sophisticated mechanism of cooperative force generation between two major forces driving morphogenesis.

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Exocytosis of post-Golgi vesicles is regulated by components of the endocytic machinery.

Publication Date: 2009 Jun 26 PMID: 19563761
Authors: Jaiswal, J. K. - Rivera, V. M. - Simon, S. M.
Journal: Cell

Post-Golgi vesicles target and deliver most biosynthetic cargoes to the cell surface. However, the molecules and mechanisms involved in fusion of these vesicles are not well understood. We have employed a system to simultaneously monitor release of luminal and membrane biosynthetic cargoes from individual post-Golgi vesicles. Exocytosis of these vesicles is not calcium triggered. Release of luminal cargo can be accompanied by complete, partial, or no release of membrane cargo. Partial and no release of membrane cargo of a fusing vesicle are fates associated with kiss-and-run exocytosis, and we find that these are the predominant mode of post-Golgi vesicle exocytosis. Partial cargo release by post-Golgi vesicles occurs because of premature closure of the fusion pore and is modulated by the activity of clathrin, actin, and dynamin. Our results demonstrate that these components of the endocytic machinery modulate the nature and extent of biosynthetic cargo delivery by post-Golgi vesicles at the cell membrane.

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Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.

Publication Date: 2009 Jun 26 PMID: 19563760
Authors: Jura, N. - Endres, N. F. - Engel, K. - Deindl, S. - Das, R. - Lamers, M. H. - Wemmer, D. E. - Zhang, X. - Kuriyan, J.
Journal: Cell

Signaling by the epidermal growth factor receptor requires an allosteric interaction between the kinase domains of two receptors, whereby one activates the other. We show that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains. The C-terminal half of the juxtamembrane segment latches the activated kinase domain to the activator, and the N-terminal half of this segment further potentiates dimerization, most likely by forming an antiparallel helical dimer that engages the transmembrane helices of the activated receptor. Our data are consistent with a mechanism in which the extracellular domains block the intrinsic ability of the transmembrane and cytoplasmic domains to dimerize and activate, with ligand binding releasing this block. The formation of the activating juxtamembrane latch is prevented by the C-terminal tails in a structure of an inactive kinase domain dimer, suggesting how alternative dimers can prevent ligand-independent activation.

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A synthetic genetic edge detection program.

Publication Date: 2009 Jun 26 PMID: 19563759
Authors: Tabor, J. J. - Salis, H. M. - Simpson, Z. B. - Chevalier, A. A. - Levskaya, A. - Marcotte, E. M. - Voigt, C. A. - Ellington, A. D.
Journal: Cell

Edge detection is a signal processing algorithm common in artificial intelligence and image recognition programs. We have constructed a genetically encoded edge detection algorithm that programs an isogenic community of E. coli to sense an image of light, communicate to identify the light-dark edges, and visually present the result of the computation. The algorithm is implemented using multiple genetic circuits. An engineered light sensor enables cells to distinguish between light and dark regions. In the dark, cells produce a diffusible chemical signal that diffuses into light regions. Genetic logic gates are used so that only cells that sense light and the diffusible signal produce a positive output. A mathematical model constructed from first principles and parameterized with experimental measurements of the component circuits predicts the performance of the complete program. Quantitatively accurate models will facilitate the engineering of more complex biological behaviors and inform bottom-up studies of natural genetic regulatory networks.

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Genomic antagonism between retinoic acid and estrogen signaling in breast cancer.

Publication Date: 2009 Jun 26 PMID: 19563758
Authors: Hua, S. - Kittler, R. - White, K. P.
Journal: Cell

Retinoic acid (RA) triggers antiproliferative effects in tumor cells, and therefore RA and its synthetic analogs have great potential as anticarcinogenic agents. Retinoic acid receptors (RARs) mediate RA effects by directly regulating gene expression. To define the genetic network regulated by RARs in breast cancer, we identified RAR genomic targets using chromatin immunoprecipitation and expression analysis. We found that RAR binding throughout the genome is highly coincident with estrogen receptor alpha (ERalpha) binding, resulting in a widespread crosstalk of RA and estrogen signaling to antagonistically regulate breast cancer-associated genes. ERalpha- and RAR-binding sites appear to be coevolved on a large scale throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements. The highly coordinated intersection between these two critical nuclear hormone receptor signaling pathways provides a global mechanism for balancing gene expression output via local regulatory interactions dispersed throughout the genome.

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Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect.

Publication Date: 2009 Jun 26 PMID: 19563757
Authors: Veatch, J. R. - McMurray, M. A. - Nelson, Z. W. - Gottschling, D. E.
Journal: Cell

Mutations and deletions in the mitochondrial genome (mtDNA), as well as instability of the nuclear genome, are involved in multiple human diseases. Here, we report that in Saccharomyces cerevisiae, loss of mtDNA leads to nuclear genome instability, through a process of cell-cycle arrest and selection we define as a cellular crisis. This crisis is not mediated by the absence of respiration, but instead correlates with a reduction in the mitochondrial membrane potential. Analysis of cells undergoing this crisis identified a defect in iron-sulfur cluster (ISC) biogenesis, which requires normal mitochondrial function. We found that downregulation of nonmitochondrial ISC protein biogenesis was sufficient to cause increased genomic instability in cells with intact mitochondrial function. These results suggest mitochondrial dysfunction stimulates nuclear genome instability by inhibiting the production of ISC-containing protein(s), which are required for maintenance of nuclear genome integrity. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data.

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Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.

Publication Date: 2009 Jun 26 PMID: 19563756
Authors: Nakatani, J. - Tamada, K. - Hatanaka, F. - Ise, S. - Ohta, H. - Inoue, K. - Tomonaga, S. - Watanabe, Y. - Chung, Y. J. - Banerjee, R. - Iwamoto, K. - Kato, T. - Okazawa, M. - Yamauchi, K. - Tanda, K. - Takao, K. - Miyakawa, T. - Bradley, A. - Takumi, T.
Journal: Cell

Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca(2+) responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.

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Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation.

Publication Date: 2009 Jun 26 PMID: 19563755
Authors: Wu, Q. - Boyle, M. P. - Palmiter, R. D.
Journal: Cell

Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.

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Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol.

Publication Date: 2009 Jun 26 PMID: 19563754
Authors: Kwon, H. J. - Abi-Mosleh, L. - Wang, M. L. - Deisenhofer, J. - Goldstein, J. L. - Brown, M. S. - Infante, R. E.
Journal: Cell

LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3beta-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3beta-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.

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CTCF: master weaver of the genome.

Publication Date: 2009 Jun 26 PMID: 19563753
Authors: Phillips, J. E. - Corces, V. G.
Journal: Cell

CTCF is a highly conserved zinc finger protein implicated in diverse regulatory functions, including transcriptional activation/repression, insulation, imprinting, and X chromosome inactivation. Here we re-evaluate data supporting these roles in the context of mechanistic insights provided by recent genome-wide studies and highlight evidence for CTCF-mediated intra- and interchromosomal contacts at several developmentally regulated genomic loci. These analyses support a primary role for CTCF in the global organization of chromatin architecture and suggest that CTCF may be a heritable component of an epigenetic system regulating the interplay between DNA methylation, higher-order chromatin structure, and lineage-specific gene expression.

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Plant asymmetric cell division, vive la difference!

Publication Date: 2009 Jun 26 PMID: 19563752
Authors: Menke, F. L. - Scheres, B.
Journal: Cell

Although little is known about how asymmetric cell division in plants is regulated, recent discoveries provide a starting point for exploring the mechanisms underlying this process. These studies reveal parallels with asymmetric division in yeast and animals, but also point to regulated cell expansion as a new mechanism of asymmetric division in plants.

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Fly stem cell research gets infectious.

Publication Date: 2009 Jun 26 PMID: 19563751
Authors: Conder, R. - Knoblich, J. A.
Journal: Cell

To maintain tissue homeostasis, stem cells need to increase their proliferation rate to repair tissue damage caused by stress or infection. In this issue, Jiang et al. (2009) describe a regulatory feedback mechanism involving the Jak/Stat signaling pathway that enables stem cells of the fly midgut to accomplish this task.

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Closing in on mechanisms of tissue morphogenesis.

Publication Date: 2009 Jun 26 PMID: 19563750
Authors: Rauzi, M. - Lecuit, T.
Journal: Cell

It remains largely unknown how large-scale tissue movements during development emerge from the interplay of different tensile forces associated with actomyosin networks. Solon et al. (2009) now report that a ratchet-like mechanism drives the movement of epithelial sheets during dorsal closure in embryos of the fruit fly Drosophila.

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The juxtamembrane region of EGFR takes center stage.

Publication Date: 2009 Jun 26 PMID: 19563749
Authors: Hubbard, S. R.
Journal: Cell

The activation process for the epidermal growth factor receptor (EGFR) involves formation of an asymmetric dimer of the tyrosine kinase domains. Jura et al. (2009) in this issue and Brewer et al. (2009) in Molecular Cell now demonstrate that the juxtamembrane region of EGFR plays a crucial role in stabilizing this dimer.

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Ironing out a midlife crisis.

Publication Date: 2009 Jun 26 PMID: 19563748
Authors: Vergara, S. V. - Thiele, D. J.
Journal: Cell

There is a strong correlation between age, genomic instability, and the development of cancer. Working in yeast, Veatch et al. (2009) now propose that defects in the biogenesis of iron-sulfur clusters arising as a consequence of mitochondrial dysfunction contribute to the increase in genomic instability as cells age.

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GABA keeps up an appetite for life.

Publication Date: 2009 Jun 26 PMID: 19563747
Authors: Dietrich, M. O. - Horvath, T. L.
Journal: Cell

In the arcuate nucleus of the hypothalamus, neurons that produce the neuropeptides NPY and AgRP play a vital role in the maintenance of energy homeostasis. In this issue, Wu et al. (2009) show that these neurons modulate feeding behavior in mice by providing GABAergic input to the parabrachial nucleus in the brainstem.

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Common ancestry of the CENP-A chaperones Scm3 and HJURP.

Publication Date: 2009 Jun 26 PMID: 19563746
Authors: Sanchez-Pulido, L. - Pidoux, A. L. - Ponting, C. P. - Allshire, R. C.
Journal: Cell

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Seeing green in conference season.

Publication Date: 2009 Jun 26 PMID: 19563745
Authors: Guterman, L.
Journal: Cell

Researchers and scientific organizations are becoming aware of the greenhouse-gas emissions and waste associated with attending scientific conferences. Fledgling efforts are now underway to address this problem by offering carbon offsets, recycling at conferences, reducing conference travel, or replacing meetings with teleconferences.

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Evolution of Genetic Networks Underlying the Emergence of Thymopoiesis in Vertebrates.

Publication Date: 2009 Jun 24 PMID: 19559469
Authors: Bajoghli, B. - Aghaallaei, N. - Hess, I. - Rode, I. - Netuschil, N. - Tay, B. H. - Venkatesh, B. - Yu, J. K. - Kaltenbach, S. L. - Holland, N. D. - Diekhoff, D. - Happe, C. - Schorpp, M. - Boehm, T.
Journal: Cell

About 500 million years ago, a new type of adaptive immune defense emerged in basal jawed vertebrates, accompanied by morphological innovations, including the thymus. Did these evolutionary novelties arise de novo or from elaboration of ancient genetic networks? We reconstructed the genetic changes underlying thymopoiesis by comparative genome and expression analyses in chordates and basal vertebrates. The derived models of genetic networks were experimentally verified in bony fishes. Ancestral networks defining circumscribed regions of the pharyngeal epithelium of jawless vertebrates expanded in cartilaginous fishes to incorporate novel genes, notably those encoding chemokines. Correspondingly, novel networks evolved in lymphocytes of jawed vertebrates to control the expression of additional chemokine receptors. These complementary changes enabled unprecedented Delta/Notch signaling between pharyngeal epithelium and lymphoid cells that was exploited for specification to the T cell lineage. Our results provide a framework elucidating the evolution of key features of the adaptive immune system in jawed vertebrates.

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SnapShot: F box proteins I.

Publication Date: 2009 Jun 12 PMID: 19524517
Authors: Skaar, J. R. - Pagan, J. K. - Pagano, M.
Journal: Cell

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Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.

Publication Date: 2009 Jun 12 PMID: 19524516
Authors: Scherrer, G. - Imamachi, N. - Cao, Y. Q. - Contet, C. - Mennicken, F. - O'Donnell, D. - Kieffer, B. L. - Basbaum, A. I.
Journal: Cell

Delta and mu opioid receptors (DORs and MORs) are inhibitory G protein-coupled receptors that reportedly cooperatively regulate the transmission of pain messages by substance P and TRPV1-expressing pain fibers. Using a DOReGFP reporter mouse we now show that the DOR and MOR are, in fact, expressed by different subsets of primary afferents. The MOR is expressed in peptidergic pain fibers, the DOR in myelinated and nonpeptidergic afferents. Contrary to the prevailing view, we demonstrate that the DOR is trafficked to the cell surface under resting conditions, independently of substance P, and internalized following activation by DOR agonists. Finally, we show that the segregated DOR and MOR distribution is paralleled by a remarkably selective functional contribution of the two receptors to the control of mechanical and heat pain, respectively. These results demonstrate that behaviorally relevant pain modalities can be selectively regulated through the targeting of distinct subsets of primary afferent pain fibers.

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Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration.

Publication Date: 2009 Jun 12 PMID: 19524515
Authors: Chakrabarti, O. - Hegde, R. S.
Journal: Cell

The pathways leading from aberrant Prion protein (PrP) metabolism to neurodegeneration are poorly understood. Some familial PrP mutants generate increased (Ctm)PrP, a transmembrane isoform associated with disease. In other disease situations, a potentially toxic cytosolic form (termed cyPrP) might be produced. However, the mechanisms by which (Ctm)PrP or cyPrP cause selective neuronal dysfunction are unknown. Here, we show that both (Ctm)PrP and cyPrP can interact with and disrupt the function of Mahogunin (Mgrn), a cytosolic ubiquitin ligase whose loss causes spongiform neurodegeneration. Cultured cells and transgenic mice expressing either (Ctm)PrP-producing mutants or cyPrP partially phenocopy Mgrn depletion, displaying aberrant lysosomal morphology and loss of Mgrn in selected brain regions. These effects were rescued by either Mgrn overexpression, competition for PrP-binding sites, or prevention of cytosolic PrP exposure. Thus, transient or partial exposure of PrP to the cytosol leads to inappropriate Mgrn sequestration that contributes to neuronal dysfunction and disease.

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The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis.

Publication Date: 2009 Jun 12 PMID: 19524514
Authors: Benedito, R. - Roca, C. - Sorensen, I. - Adams, S. - Gossler, A. - Fruttiger, M. - Adams, R. H.
Journal: Cell

The Notch pathway is a highly conserved signaling system that controls a diversity of growth, differentiation, and patterning processes. In growing blood vessels, sprouting of endothelial tip cells is inhibited by Notch signaling, which is activated by binding of the Notch receptor to its ligand Delta-like 4 (Dll4). Here, we show that the Notch ligand Jagged1 is a potent proangiogenic regulator in mice that antagonizes Dll4-Notch signaling in cells expressing Fringe family glycosyltransferases. Upon glycosylation of Notch, Dll4-Notch signaling is enhanced, whereas Jagged1 has weak signaling capacity and competes with Dll4. Our findings establish that the equilibrium between two Notch ligands with distinct spatial expression patterns and opposing functional roles regulates angiogenesis, a mechanism that might also apply to other Notch-controlled biological processes.

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Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation.

Publication Date: 2009 Jun 12 PMID: 19524513
Authors: Cho, Y. S. - Challa, S. - Moquin, D. - Genga, R. - Ray, T. D. - Guildford, M. - Chan, F. K.
Journal: Cell

Programmed necrosis is a form of caspase-independent cell death whose molecular regulation is poorly understood. The kinase RIP1 is crucial for programmed necrosis, but also mediates activation of the prosurvival transcription factor NF-kappaB. We postulated that additional molecules are required to specifically activate programmed necrosis. Using a RNA interference screen, we identified the kinase RIP3 as a crucial activator for programmed necrosis induced by TNF and during virus infection. RIP3 regulates necrosis-specific RIP1 phosphorylation. The phosphorylation of RIP1 and RIP3 stabilizes their association within the pronecrotic complex, activates the pronecrotic kinase activity, and triggers downstream reactive oxygen species production. The pronecrotic RIP1-RIP3 complex is induced during vaccinia virus infection. Consequently, RIP3(-/-) mice exhibited severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication. Our findings suggest that RIP3 controls programmed necrosis by initiating the pronecrotic kinase cascade, and that this is necessary for the inflammatory response against virus infections.

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Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha.

Publication Date: 2009 Jun 12 PMID: 19524512
Authors: He, S. - Wang, L. - Miao, L. - Wang, T. - Du, F. - Zhao, L. - Wang, X.
Journal: Cell

Smac mimetics induce apoptosis synergistically with TNF-alpha by triggering the formation of a caspase-8-activating complex containing receptor interacting protein kinase-1 (RIPK1). Caspase inhibitors block this form of apoptosis in many types of cells. However, in several other cell lines, caspase inhibitors switch the apoptotic response to necrosis. A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. The expression of RIP3 in different cell lines correlates with their responsiveness to necrosis induction. The kinase activity of RIP3 is essential for necrosis execution. Upon induction of necrosis, RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. Embryonic fibroblasts from RIP3 knockout mice are resistant to necrosis and RIP3 knockout animals are devoid of inflammation inflicted tissue damage in an acute pancreatitis model. These data indicate RIP3 as the determinant for cellular necrosis in response to TNF-alpha family of death-inducing cytokines.

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Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation.

Publication Date: 2009 Jun 12 PMID: 19524511
Authors: Inomata, K. - Aoto, T. - Binh, N. T. - Okamoto, N. - Tanimura, S. - Wakayama, T. - Iseki, S. - Hara, E. - Masunaga, T. - Shimizu, H. - Nishimura, E. K.
Journal: Cell

Somatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a "stemness checkpoint" to maintain the stem cell quality and quantity.

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Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation.

Publication Date: 2009 Jun 12 PMID: 19524510
Authors: Rogowski, K. - Juge, F. - van Dijk, J. - Wloga, D. - Strub, J. M. - Levilliers, N. - Thomas, D. - Bre, M. H. - Van Dorsselaer, A. - Gaertig, J. - Janke, C.
Journal: Cell

Polyglycylation is a posttranslational modification that generates glycine side chains on proteins. Here we identify a family of evolutionarily conserved glycine ligases that modify tubulin using different enzymatic mechanisms. In mammals, two distinct enzyme types catalyze the initiation and elongation steps of polyglycylation, whereas Drosophila glycylases are bifunctional. We further show that the human elongating glycylase has lost enzymatic activity due to two amino acid changes, suggesting that the functions of protein glycylation could be sufficiently fulfilled by monoglycylation. Depletion of a glycylase in Drosophila using RNA interference results in adult flies with strongly decreased total glycylation levels and male sterility associated with defects in sperm individualization and axonemal maintenance. A more severe RNAi depletion is lethal at early developmental stages, indicating that protein glycylation is essential. Together with the observation that multiple proteins are glycylated, our functional data point towards a general role of glycylation in protein functions.

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Autophagy suppresses tumorigenesis through elimination of p62.

Publication Date: 2009 Jun 12 PMID: 19524509
Authors: Mathew, R. - Karp, C. M. - Beaudoin, B. - Vuong, N. - Chen, G. - Chen, H. Y. - Bray, K. - Reddy, A. - Bhanot, G. - Gelinas, C. - Dipaola, R. S. - Karantza-Wadsworth, V. - White, E.
Journal: Cell

Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kappaB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.

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Cyfip1 is a putative invasion suppressor in epithelial cancers.

Publication Date: 2009 Jun 12 PMID: 19524508
Authors: Silva, J. M. - Ezhkova, E. - Silva, J. - Heart, S. - Castillo, M. - Campos, Y. - Castro, V. - Bonilla, F. - Cordon-Cardo, C. - Muthuswamy, S. K. - Powers, S. - Fuchs, E. - Hannon, G. J.
Journal: Cell

Identification of bona fide tumor suppressors is often challenging because of the large number of genetic alterations present in most human cancers. To evaluate candidate genes present within chromosomal regions recurrently deleted in human cancers, we coupled high-resolution genomic analysis with a two-stage genetic study using RNA interference (RNAi). We found that Cyfip1, a subunit of the WAVE complex, which regulates cytoskeletal dynamics, is commonly deleted in human epithelial cancers. Reduced expression of CYFIP1 is commonly observed during invasion of epithelial tumors and is associated with poor prognosis in this setting. Silencing of Cyfip1 disturbed normal epithelial morphogenesis in vitro and cooperated with oncogenic Ras to produce invasive carcinomas in vivo. Mechanistically, we have linked alterations in WAVE-regulated actin dynamics with impaired cell-cell adhesion and cell-ECM interactions. Thus, we propose Cyfip1 as an invasion suppressor gene.

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A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis.

Publication Date: 2009 Jun 12 PMID: 19524507
Authors: Valastyan, S. - Reinhardt, F. - Benaich, N. - Calogrias, D. - Szasz, A. M. - Wang, Z. C. - Brock, J. E. - Richardson, A. L. - Weinberg, R. A.
Journal: Cell

MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.

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Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling.

Publication Date: 2009 Jun 12 PMID: 19524506
Authors: Xu, X. L. - Fang, Y. - Lee, T. C. - Forrest, D. - Gregory-Evans, C. - Almeida, D. - Liu, A. - Jhanwar, S. C. - Abramson, D. H. - Cobrinik, D.
Journal: Cell

Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRgamma transcription factor and a human-specific RXRgamma consensus binding site, and proliferation required RXRgamma, as well as the cone-specific thyroid hormone receptor-beta2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.

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Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model.

Publication Date: 2009 Jun 12 PMID: 19524505
Authors: Kota, J. - Chivukula, R. R. - O'Donnell, K. A. - Wentzel, E. A. - Montgomery, C. L. - Hwang, H. W. - Chang, T. C. - Vivekanandan, P. - Torbenson, M. - Clark, K. R. - Mendell, J. R. - Mendell, J. T.
Journal: Cell

Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.

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p62 at the crossroads of autophagy, apoptosis, and cancer.

Publication Date: 2009 Jun 12 PMID: 19524504
Authors: Moscat, J. - Diaz-Meco, M. T.
Journal: Cell

The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor NF-kappaB. Recent findings link p62 activity to the extrinsic apoptosis pathway, and Mathew et al. (2009) now show that the modulation of p62 by autophagy is a key factor in tumorigenesis. These findings place p62 at critical decision points that control cell death and survival.

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Bridging physiology and pathology in AD.

Publication Date: 2009 Jun 12 PMID: 19524503
Authors: Kim, D. - Tsai, L. H.
Journal: Cell

The APP-processing pathway is a pathological component of Alzheimer's disease (AD), but there is no consensus regarding the physiological functions of APP and its products. Two studies (Nikolaev et al., 2009; Lauren et al., 2009) link the physiological and pathological aspects of APP processing. They show that the APP products, N-APP and Abeta42, are ligands for death receptor 6 and cellular prion protein, respectively, which are important in nervous system development and synaptic suppression.

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Prion topology and toxicity.

Publication Date: 2009 Jun 12 PMID: 19524502
Authors: Aguzzi, A. - Steele, A. D.
Journal: Cell

Inactivation of mahogunin, an E3 ubiquitin ligase, causes a spongiform encephalopathy resembling prion disease. Chakrabarti and Hegde (2009) now report that prion proteins with aberrant topologies inactivate mahogunin, providing a plausible explanation for certain aspects of prion pathology.

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Retinoblastoma, an inside job.

Publication Date: 2009 Jun 12 PMID: 19524501
Authors: Bremner, R.
Journal: Cell

Why are some cell types more prone to transformation than others? In this issue, Xu et al. (2009) show that retinoblastoma cells co-opt several intrinsic features of cone photoreceptors for their survival and growth.

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New hope for a microRNA therapy for liver cancer.

Publication Date: 2009 Jun 12 PMID: 19524500
Authors: Rossi, J. J.
Journal: Cell

The loss of expression of particular microRNAs can contribute to tumorigenesis. Kota et al. (2009) now explore in a mouse model a promising new approach for the treatment of liver cancer-re-establishing the expression of an miRNA using a viral vector.

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Jagged gives endothelial tip cells an edge.

Publication Date: 2009 Jun 12 PMID: 19524499
Authors: Suchting, S. - Eichmann, A.
Journal: Cell

Sprouting blood vessels have tip cells that lead and stalk cells that follow. Benedito et al. (2009) now show that competition between endothelial cells for the tip position is regulated by glycosylation of Notch receptors and by the opposing actions of the Notch ligands Jagged1 and Delta-like 4.

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Mu and delta opioid receptors diverge.

Publication Date: 2009 Jun 12 PMID: 19524498
Authors: Woolf, C. J.
Journal: Cell

Contrary to current models, Scherrer et al. (2009) provide evidence that mu and delta opioid receptors are not expressed by the same pain-sensing neurons. In mice, agonists for these receptors produce analgesia restricted to either noxious heat or mechanical stimuli, implying that the receptors act on distinct fibers to mediate completely different types of pain relief.

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Unraveling the mystery of swine influenza virus.

Publication Date: 2009 Jun 12 PMID: 19524497
Authors: Wang, T. T. - Palese, P.
Journal: Cell

Influenza virus outbreaks occur with regularity, but the severity of outbreaks is not consistent. The recent flu epidemic caused by an H1N1 swine influenza virus presents an opportunity to examine what is known about virulence factors and the spread of infection to better prepare for major influenza outbreaks in the future.

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X-ray structures of the hexameric building block of the HIV capsid.

Publication Date: 2009 Jun 26 PMID: 19523676
Authors: Pornillos, O. - Ganser-Pornillos, B. K. - Kelly, B. N. - Hua, Y. - Whitby, F. G. - Stout, C. D. - Sundquist, W. I. - Hill, C. P. - Yeager, M.
Journal: Cell

The mature capsids of HIV and other retroviruses organize and package the viral genome and its associated enzymes for delivery into host cells. The HIV capsid is a fullerene cone: a variably curved, closed shell composed of approximately 250 hexamers and exactly 12 pentamers of the viral CA protein. We devised methods for isolating soluble, assembly-competent CA hexamers and derived four crystallographically independent models that define the structure of this capsid assembly unit at atomic resolution. A ring of six CA N-terminal domains form an apparently rigid core, surrounded by an outer ring of C-terminal domains. Mobility of the outer ring appears to be an underlying mechanism for generating the variably curved lattice in authentic capsids. Hexamer-stabilizing interfaces are highly hydrated, and this property may be key to the formation of quasi-equivalent interactions within hexamers and pentamers. The structures also clarify the molecular basis for capsid assembly inhibition and should facilitate structure-based drug design strategies.

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BASL controls asymmetric cell division in Arabidopsis.

Publication Date: 2009 Jun 26 PMID: 19523675
Authors: Dong, J. - MacAlister, C. A. - Bergmann, D. C.
Journal: Cell

Development in multicellular organisms requires the organized generation of differences. A universal mechanism for creating such differences is asymmetric cell division. In plants, as in animals, asymmetric divisions are correlated with the production of cellular diversity and pattern; however, structural constraints imposed by plant cell walls and the absence of homologs of known animal or fungal cell polarity regulators necessitates that plants utilize new molecules and mechanisms to create asymmetries. Here, we identify BASL, a novel regulator of asymmetric divisions in Arabidopsis. In asymmetrically dividing stomatal-lineage cells, BASL accumulates in a polarized crescent at the cell periphery before division, and then localizes differentially to the nucleus and a peripheral crescent in self-renewing cells and their sisters after division. BASL presence at the cell periphery is critical for its function, and we propose that BASL represents a plant-specific solution to the challenge of asymmetric cell division.

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