Latest Articles Include:
- Demystifying peer review
- Nature Cell Biology 12(5):413 (2010)
Peer review is an essential aspect of the publishing process; journals and the research community have a shared interest in it being a constructive process. - Nature Communications
- Nature Cell Biology 12(5):413 (2010)
A new Nature research journal for the biological, physical and chemical sciences. - The Annotated Darwin
- Nature Cell Biology 12(5):414 (2010)
Who has not found joy, surprise, and intellectual ferment upon reading a book with "The Annotated..." in the title? The Annotated Mother Goose, The Annotated Alice, The Annotated Sherlock Holmes, and even The Annotated Grateful Dead Lyrics project provide breadth and depth that only serve to expand our experience, understanding and appreciation of works we thought we knew so well. - Signalling lessons from death receptors: the importance of cleavage
- Nature Cell Biology 12(5):415 (2010)
The place was Ann Arbor, University of Michigan, in the spring of 1994. Three years earlier, I had switched from studying extracellular matrix proteins to investigating how death receptors induced apoptosis. - Cracking CRAC
- Nature Cell Biology 12(5):416-418 (2010)
CRACR2A is a newly discovered Ca2+-binding protein that regulates store-operated Ca2+ entry (SOCE). CRACR2A enhances SOCE by promoting the binding of the endoplasmic reticulum Ca2+ sensor STIM to Orai, a Ca2+ channel located in the plasma membrane. As intracellular Ca2+ levels rise, CRACR2A binds Ca2+ and triggers SOCE inactivation by dissociating from the Orai–STIM complex. - Cancer stem cells: nature versus nurture
Korkaya H Wicha MS - Nature Cell Biology 12(5):419-421 (2010)
Although all cells within a colon cancer may harbour adenomatous polyposis coli (APC) or β-catenin mutations, activation of Wnt signalling is limited to a subpopulation of cells that display cancer stem cell properties. This activation requires a co-stimulatory signal mediated by hepatocyte growth factor, which is produced by tumour-associated myofibroblasts. - Division of labour in ESCRT complexes
- Nature Cell Biology 12(5):422-423 (2010)
Formation of multivesicular bodies (MVBs) from endosomes or budding of enveloped virus such as HIV-I from the plasma membrane require the ESCRT (endosomal sorting complex required for transport) complexes. An in vitro reconstitution assay unambiguously identifies the function of each ESCRT complex in the sequential events of MVB morphogenesis, from cargo clustering and membrane bud formation to sequestration of cargoes in vesicles, and fission of the vesicles into the lumen of the endosome. - A mitotic role for the DNA damage-responsive CHK2 kinase
- Nature Cell Biology 12(5):424-425 (2010)
Instability in the structure and number of chromosomes is a trait common to cells from most epithelial cancers. A role in chromosome segregation for a pathway previously implicated in the DNA damage response reveals new connections between the tumour suppressive processes that maintain chromosome integrity. - Research highlights
- Nature Cell Biology 12(5):426 (2010)
USP9x makes the junctions tight Epigenetic regulation and miRNA crosstalk. Rab11 promotes primary ciliogenesis Signalling? Use the Force! - Electron tomography reveals unbranched networks of actin filaments in lamellipodia
Urban E Jacob S Nemethova M Resch GP Small JV - Nature Cell Biology 12(5):429-435 (2010)
Eukaryotic cells can initiate movement using the forces exerted by polymerizing actin filaments to extend lamellipodial and filopodial protrusions. In the current model, actin filaments in lamellipodia are organized in a branched, dendritic network. We applied electron tomography to vitreously frozen 'live' cells, fixed cells and cytoskeletons, embedded in vitreous ice or in deep-negative stain. In lamellipodia from four cell types, including rapidly migrating fish keratocytes, we found that actin filaments are almost exclusively unbranched. The vast majority of apparent filament junctions proved to be overlapping filaments, rather than branched end-to-side junctions. Analysis of the tomograms revealed that actin filaments terminate at the membrane interface within a zone several hundred nanometres wide at the lamellipodium front, and yielded the first direct measurements of filament densities. Actin filament pairs were also identified as lamellipodium components and b! undle precursors. These data provide a new structural basis for understanding actin-driven protrusion during cell migration. - A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells
Srikanth S Jung HJ Kim KD Souda P Whitelegge J Gwack Y - Nature Cell Biology 12(5):436-446 (2010)
Orai1 and STIM1 are critical components of Ca2+ release-activated Ca2+ (CRAC) channels that mediate store-operated Ca2+ entry (SOCE) in immune cells. Although it is known that Orai1 and STIM1 co-cluster and physically interact to mediate SOCE, the cytoplasmic machinery modulating these functions remains poorly understood. We sought to find modulators of Orai1 and STIM1 using affinity protein purification and identified a novel EF-hand protein, CRACR2A (also called CRAC regulator 2A, EFCAB4B or FLJ33805). We show that CRACR2A interacts directly with Orai1 and STIM1, forming a ternary complex that dissociates at elevated Ca2+ concentrations. Studies using knockdown mediated by small interfering RNA (siRNA) and mutagenesis show that CRACR2A is important for clustering of Orai1 and STIM1 upon store depletion. Expression of an EF-hand mutant of CRACR2A enhanced STIM1 clustering, elevated cytoplasmic Ca2+ and induced cell death, suggesting its active interaction with CRAC ch! annels. These observations implicate CRACR2A, a novel Ca2+ binding protein that is highly expressed in T cells and conserved in vertebrates, as a key regulator of CRAC channel-mediated SOCE. - Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control
Novoa I Gallego J Ferreira PG Mendez R - Nature Cell Biology 12(5):447-456 (2010)
Meiotic and early-embryonic cell divisions in vertebrates take place in the absence of transcription and rely on the translational regulation of stored maternal messenger RNAs. Most of these mRNAs are regulated by the cytoplasmic-polyadenylation-element-binding protein (CPEB), which mediates translational activation and repression through cytoplasmic changes in their poly(A) tail length. It was unknown whether translational regulation by cytoplasmic polyadenylation and CPEB can also regulate mRNAs at specific points of mitotic cell-cycle divisions. Here we show that CPEB-mediated post-transcriptional regulation by phase-specific changes in poly(A) tail length is required for cell proliferation and specifically for entry into M phase in mitotically dividing cells. This translational control is mediated by two members of the CPEB family of proteins, CPEB1 and CPEB4. We conclude that regulation of poly(A) tail length is not only required to compensate for the lack of tran! scription in specialized cell divisions but also acts as a general mechanism to control mitosis. - Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis
Chan CH Lee SW Li CF Wang J Yang WL Wu CY Wu J Nakayama KI Kang HY Huang HY Hung MC Pandolfi PP Lin HK - Nature Cell Biology 12(5):457-467 (2010)
The RhoA GTPase is crucial in numerous biological functions and is linked to cancer metastasis. However, the understanding of the molecular mechanism responsible for RhoA transcription is still very limited. Here we show that RhoA transcription is orchestrated by the Myc–Skp2–Miz1–p300 transcriptional complex. Skp2 cooperates with Myc to induce RhoA transcription by recruiting Miz1 and p300 to the RhoA promoter independently of Skp1-Cullin-F-box protein containing complex (SCF)–Skp2 E3 ligase activity. Deficiency of this complex results in impairment in RhoA expression, cell migration, invasion, and breast cancer metastasis, recapitulating the phenotypes observed in RhoA knockdown, and RhoA restoration rescues the defect in cell invasion. Overexpression of the Myc–Skp2–Miz1 complex is found in metastatic human cancers and is correlated with RhoA expression. Our study provides insight into how oncogenic Skp2 and Myc coordinate to induce RhoA transcription an! d establishes a novel SCF–Skp2 E3-ligase-independent function for oncogenic Skp2 in transcription and cancer metastasis. - Wnt activity defines colon cancer stem cells and is regulated by the microenvironment
Vermeulen L De Sousa E Melo F van der Heijden M Cameron K de Jong JH Borovski T Tuynman JB Todaro M Merz C Rodermond H Sprick MR Kemper K Richel DJ Stassi G Medema JP - Nature Cell Biology 12(5):468-476 (2010)
Despite the presence of mutations in APC or β-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when β-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate β-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both in vitro a! nd in vivo. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity. - Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1
Boulter E Garcia-Mata R Guilluy C Dubash A Rossi G Brennwald PJ Burridge K - Nature Cell Biology 12(5):477-483 (2010)
At steady state, most Rho GTPases are bound in the cytosol to Rho guanine nucleotide dissociation inhibitors (RhoGDIs)1. RhoGDIs have generally been considered to hold Rho proteins passively in an inactive state within the cytoplasm. Here we describe an evolutionarily conserved mechanism by which RhoGDI1 controls the homeostasis of Rho proteins in eukaryotic cells. We found that depletion of RhoGDI1 promotes misfolding and degradation of the cytosolic geranylgeranylated pool of Rho GTPases while activating the remaining membrane-bound fraction. Because RhoGDI1 levels are limiting, and Rho proteins compete for binding to RhoGDI1, overexpression of an exogenous Rho GTPase displaces endogenous Rho proteins bound to RhoGDI1, inducing their degradation and inactivation. These results raise important questions about the conclusions drawn from studies that manipulate Rho protein levels. In many cases the response observed may arise not simply from the overexpression itself bu! t from additional effects on the levels and activity of other Rho GTPases as a result of competition for binding to RhoGDI1; this may require a re-evaluation of previously published studies that rely exclusively on these techniques. - GEMC1 is a TopBP1-interacting protein required for chromosomal DNA replication
Balestrini A Cosentino C Errico A Garner E Costanzo V - Nature Cell Biology 12(5):484-491 (2010)
Many of the factors required for chromosomal DNA replication have been identified in unicellular eukaryotes. However, DNA replication is poorly understood in multicellular organisms. Here, we report the identification of GEMC1 (geminin coiled-coil containing protein 1), a novel vertebrate protein required for chromosomal DNA replication. GEMC1 is highly conserved in vertebrates and is preferentially expressed in proliferating cells. Using Xenopus laevis egg extract we show that Xenopus GEMC1 (xGEMC1) binds to the checkpoint and replication factor TopBP1, which promotes binding of xGEMC1 to chromatin during pre-replication complex (pre-RC) formation. We demonstrate that xGEMC1 interacts directly with replication factors such as Cdc45 and the kinase Cdk2–CyclinE, through which it is heavily phosphorylated. Phosphorylated xGEMC1 stimulates initiation of DNA replication, whereas depletion of xGEMC1 prevents the onset of DNA replication owing to the impairment of Cdc45 lo! ading onto chromatin. Similarly, inhibition of GEMC1 expression with morpholino and siRNA oligos prevents DNA replication in embryonic and somatic vertebrate cells. These data suggest that GEMC1 promotes initiation of chromosomal DNA replication in multicellular organisms by mediating TopBP1- and Cdk2-dependent recruitment of Cdc45 onto replication origins. - The CHK2–BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells
Stolz A Ertych N Kienitz A Vogel C Schneider V Fritz B Jacob R Dittmar G Weichert W Petersen I Bastians H - Nature Cell Biology 12(5):492-499 (2010)
Chromosomal instability (CIN) is a major hallmark of human cancer and might contribute to tumorigenesis1. Genes required for the normal progression of mitosis represent potential CIN genes and, as such, are important tumour suppressors. The Chk2 kinase and its downstream targets p53 and Brca1 are tumour suppressors that have been functionally linked to the DNA damage response pathway2. Here, we report a function of Chk2, independent of p53 and DNA damage, that is required for proper progression of mitosis, and for the maintenance of chromosomal stability in human somatic cells. Depletion of Chk2 or abrogation of its kinase activity causes abnormal mitotic spindle assembly associated with a delay in mitosis, which promotes the generation of lagging chromosomes, chromosome missegregation and CIN, while still allowing survival and growth. Furthermore, we have identified Brca1 as a mitotic target of the Chk2 kinase in the absence of DNA damage. Accordingly, loss of BRCA1 o! r its Chk2-mediated phosphorylation leads to spindle formation defects and CIN. Thus, the CHK2–BRCA1 tumour suppressor pathway is required for chromosomal stability, which might contribute to their tumour suppressor function. - Shugoshin–PP2A counteracts casein-kinase-1-dependent cleavage of Rec8 by separase
Ishiguro T Tanaka K Sakuno T Watanabe Y - Nature Cell Biology 12(5):500-506 (2010)
During meiosis, the cohesin complexes that maintain sister chromatid cohesion are lost in a stepwise manner1, 2. At meiosis I the cohesin subunit Rec8 is cleaved only along the chromosome arms; until meiosis II it is protected at centromeres by the action of shugoshin (Sgo1)–protein phosphatase 2A (PP2A)3, 4, 5. Although this regulation hypothetically involves phosphorylation that is antagonized by Sgo1–PP2A, the kinase and substrate that are responsible are as yet unknown6, 7. Using a genetic screen for 'anti-shugoshin', we identify Hhp2, an orthologue of casein kinase 1δ/ε (CK1), as a factor required for Rec8 cleavage in fission yeast. We show that CK1, rather than a Polo-like kinase that is widely believed to do so, acts as the cohesin kinase to promote this cleavage during meiosis. Crucially, forced localization of excess Hhp2 at the pericentromeric region abrogates the ability of Sgo1–PP2A to protect centromeric Rec8. Thus, our studies prove the key notion! that the balance between Rec8 phosphorylation and its dephosphorylation by Sgo1–PP2A regulates the step-wise loss of chromosomal cohesion in meiosis. - Mechanosensitive gating of CFTR
- Nature Cell Biology 12(5):507-512 (2010)
Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion and intracellular ligand-gated channel associated with cystic fibrosis, a lethal genetic disorder common among Caucasians1. Here we show that CFTR is robustly activated by membrane stretch induced by negative pressures as small as 5 mmHg at the single-channel, cellular and tissue levels. Stretch increased the product of the number of channels present and probability of being open (NPo), and also increased the unitary conductance of CFTR in cell-attached membrane patches. CFTR stretch-mediated activation appears to be an intrinsic property independent of cytosolic factors and kinase signalling. CFTR stretch-mediated activation resulted in chloride transport in Calu-3 human airway epithelial cells and mouse intestinal tissues. Our study has revealed an unexpected function of CFTR in mechanosensing, in addition to its roles as a ligand-gated anion channel1 and a regulator of other membrane transporters! 2, demonstrating for the first time a mechanosensitive anion channel with a clearly defined molecular identity. Given that CFTR is often found in mechanically dynamic environments, its mechanosensitivity has important physiological implications in epithelial ion transport and cell volume regulation in vivo. - miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator
Lagos D Pollara G Henderson S Gratrix F Fabani M Milne RS Gotch F Boshoff C - Nature Cell Biology 12(5):513-519 (2010)
MicroRNAs are small, non-coding RNAs that negatively regulate gene expression1. It has been proposed that microRNAs could function in the regulation of innate immunity2, 3, but this has not been demonstrated for viral infection. Here we test this hypothesis using the human pathogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells4 (LECs). We show that an early antiviral microRNA response (6 h post-infection) includes expression of microRNAs that enhance viral gene expression. In particular, the CREB-induced miR-132 microRNA is highly upregulated after infection and has a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. We show a similar function for miR-132 during infection of monocytes with herpes simplex virus-1 (HSV-1) and human cytomegalovirus (HCMV). miR-132 regulates innate antiviral immunity by inhibiting expression of the ! p300 transcriptional co-activator. p300 is downregulated early after KSHV infection, and inhibition of miR-132 induction restores p300 expression. Furthermore, p300 regulates miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. By targeting p300, rather than a transcription factor or signalling protein, miR-132 has a broad role in the regulation of antiviral immunity. - Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia
- Nature Cell Biology 12(5):520 (2010)
Introduction ; published online 21 March 2010; corrected after print, 26 March 2010 In the version of this article initially published online and in print, there was an error in the numbering of authors who contributed equally. The corrected numbering should be as follows: Boris Guirao1,2,7, Alice Meunier1,7, Mireille Montcouquiol6,8, Kazunobu Sawamoto3,8 and Nathalie Spassky1,9 7,8These authors contributed equally to this work. 9Correspondence should be addressed to N.S. (e-mail: e-mail: spassky@biologie.ens.fr) This error has been corrected in both the HTML and PDF versions of the article. - A two-step model for senescence triggered by a single critically short telomere
- Nature Cell Biology 12(5):520 (2010)
Introduction ; published online 13 July 2009; corrected after print, 24 March 2010 In the version of this letter initially published online and in print, the labels '0 block' and '2 block' in Fig. 2a were swapped. The correct version of this figure is shown below. This error has been corrected in both the HTML and PDF versions of the article. - Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signalling during clathrin–AP-1-coated carrier biogenesis at the TGN
- Nature Cell Biology 12(5):520 (2010)
Introduction ; published online 14 March 2010; corrected after print, 22 March 2010 In the version of this article initially published online and in print, 'LAMP-1' was incorrectly written as 'LAMP-2'. The definition of AP-1 has been corrected to 'adaptor protein 1' from 'activator protein'. The following sentence has been added to the acknowledgements 'T.Kirchhausen's research was supported by the NIH grant GM075252.' These errors have been corrected in both the HTML and PDF versions of the article.
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