Latest Articles Include:
- In This Issue
- Cell 137(6):975, 977 (2009)
- Molecular Biology Select
- Cell 137(6):979, 981 (2009)
Although genomic rearrangements can have detrimental consequences, they are intentionally triggered in certain contexts such as nuclear maturation and immune evasion in protozoa, adaptation to environmental stress in bacteria, and immune system development in vertebrates. This Molecular Biology Select describes recent advances in the understanding of genomic rearrangements that benefit an organism. - Unraveling the Mystery of Swine Influenza Virus
Wang TT Palese P - Cell 137(6):983-985 (2009)
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. - Mu and Delta Opioid Receptors Diverge
Woolf CJ - Cell 137(6):987-988 (2009)
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. - Jagged Gives Endothelial Tip Cells an Edge
Suchting S Eichmann A - Cell 137(6):988-990 (2009)
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. - New Hope for a MicroRNA Therapy for Liver Cancer
Rossi JJ - Cell 137(6):990-992 (2009)
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. - Retinoblastoma, an Inside Job
Bremner R - Cell 137(6):992-994 (2009)
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. - Prion Topology and Toxicity
Aguzzi A Steele AD - Cell 137(6):994-996 (2009)
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. - Bridging Physiology and Pathology in AD
Kim D Tsai LH - Cell 137(6):997-1000 (2009)
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] and [Lauren et al., 2009]) link the physiological and pathological aspects of APP processing. They show that the APP products, N-APP and Aβ42, are ligands for death receptor 6 and cellular prion protein, respectively, which are important in nervous system development and synaptic suppression. - p62 at the Crossroads of Autophagy, Apoptosis, and Cancer
Moscat J Diaz-Meco MT - Cell 137(6):1001-1004 (2009)
The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor NF-κB. 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. - Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model
Kota J Chivukula RR O'Donnell KA Wentzel EA Montgomery CL Hwang HW Chang TC Vivekanandan P Torbenson M Clark KR Mendell JR Mendell JT - Cell 137(6):1005-1017 (2009)
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. - Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling
Xu XL Fang Y Lee TC Forrest D Gregory-Evans C Almeida D Liu A Jhanwar SC Abramson DH Cobrinik D - Cell 137(6):1018-1031 (2009)
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 RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ, as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signalin g circuitry sensitizes to the oncogenic effects of RB1 mutations. - A Pleiotropically Acting MicroRNA, miR-31, Inhibits Breast Cancer Metastasis
Valastyan S Reinhardt F Benaich N Calogrias D Szász AM Wang ZC Brock JE Richardson AL Weinberg RA - Cell 137(6):1032-1046 (2009)
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-pro moting 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. - Cyfip1 Is a Putative Invasion Suppressor in Epithelial Cancers
Silva JM Ezhkova E Silva J Heart S Castillo M Campos Y Castro V Bonilla F Cordon-Cardo C Muthuswamy SK Powers S Fuchs E Hannon GJ - Cell 137(6):1047-1061 (2009)
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. - Autophagy Suppresses Tumorigenesis through Elimination of p62
Mathew R Karp CM Beaudoin B Vuong N Chen G Chen HY Bray K Reddy A Bhanot G Gelinas C Dipaola RS Karantza-Wadsworth V White E - Cell 137(6):1062-1075 (2009)
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-κB 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 tumorige nesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis. - Evolutionary Divergence of Enzymatic Mechanisms for Posttranslational Polyglycylation
Rogowski K Juge F van Dijk J Wloga D Strub JM Levilliers N Thomas D Bré MH Van Dorsselaer A Gaertig J Janke C - Cell 137(6):1076-1087 (2009)
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 mult iple proteins are glycylated, our functional data point towards a general role of glycylation in protein functions. - Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation
Inomata K Aoto T Binh NT Okamoto N Tanimura S Wakayama T Iseki S Hara E Masunaga T Shimizu H Nishimura EK - Cell 137(6):1088-1099 (2009)
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. - Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
He S Wang L Miao L Wang T Du F Zhao L Wang X - Cell 137(6):1100-1111 (2009)
Smac mimetics induce apoptosis synergistically with TNF-α 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 respons e to TNF-α family of death-inducing cytokines. - Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation
Cho YS Challa S Moquin D Genga R Ray TD Guildford M Chan FK - Cell 137(6):1112-1123 (2009)
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-κB. 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 sugge st that RIP3 controls programmed necrosis by initiating the pronecrotic kinase cascade, and that this is necessary for the inflammatory response against virus infections. - The Notch Ligands Dll4 and Jagged1 Have Opposing Effects on Angiogenesis
Benedito R Roca C Sörensen I Adams S Gossler A Fruttiger M Adams RH - Cell 137(6):1124-1135 (2009)
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. - Functional Depletion of Mahogunin by Cytosolically Exposed Prion Protein Contributes to Neurodegeneration
Chakrabarti O Hegde RS - Cell 137(6):1136-1147 (2009)
The pathways leading from aberrant Prion protein (PrP) metabolism to neurodegeneration are poorly understood. Some familial PrP mutants generate increased CtmPrP, 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 CtmPrP or cyPrP cause selective neuronal dysfunction are unknown. Here, we show that both CtmPrP 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 CtmPrP-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 c ytosol leads to inappropriate Mgrn sequestration that contributes to neuronal dysfunction and disease. - Dissociation of the Opioid Receptor Mechanisms that Control Mechanical and Heat Pain
Scherrer G Imamachi N Cao YQ Contet C Mennicken F O'Donnell D Kieffer BL Basbaum AI - Cell 137(6):1148-1159 (2009)
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 distinc t subsets of primary afferent pain fibers. - SnapShot: F Box Proteins I
Skaar JR Pagan JK Pagano M - Cell 137(6):1160-1160.e1 (2009)
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