Latest Articles Include:
- In This Issue
- Cell 137(5):785, 787 (2009)
- Plant Biology Select
- Cell 137(5):789, 791 (2009)
With a growing body of genomic information and ever-increasing demands on agriculture, the study of plant genetics is perhaps more urgent than ever. This issue's Plant Biology Select discusses a technique for site-specific modification of crop plant genomes and describes surprising new evidence that plant tissue grafts may serve as a conduit for the spread of genetic information. Recent work also examines the basis for hybrid vigor and stress resistance in rice, and other findings provide a glimpse into the mysterious world of epigenetic inheritance. - Mind the Gap: Bringing Scientists and Society Together
Guinovart JJ - Cell 137(5):793-795 (2009)
By consolidating scientific societies into a confederation, Spanish scientists have developed a powerful platform from which to promote the importance of scientific research and science education to both the general public and government. - Finding and Drugging the Vulnerabilities of RAS-Dependent Cancers
Sawyers CL - Cell 137(5):796-798 (2009)
Kinase inhibitors have ushered in the era of targeted therapy, but their utility to date is primarily limited to cancers bearing oncogenic kinase mutations. Two papers in this issue ([Luo et al., 2009] and [Scholl et al., 2009]) could change this landscape by uncovering kinase-specific vulnerabilities in tumors with RAS mutations. - Size and Speed Go Hand in Hand in Cytokinesis
Wühr M Mitchison TJ Field CM - Cell 137(5):798-800 (2009)
In animal cells, cytokinesis is mediated by the constriction of a cortical ring. In this issue, Carvalho et al. (2009) show in embryos of the worm Caenorhabditis elegans that the rate of ring constriction during cytokinesis is proportional to the initial cell perimeter, ensuring that the duration of cytokinesis is cell-size independent. - FOXP2 and Human Cognition
Lieberman P - Cell 137(5):800-802 (2009)
Using a mouse model, Enard et al. (2009) show that the human form of the FOXP2 gene increases synaptic plasticity and dendrite connectivity in the basal ganglia. These results partly explain the enhanced capability of cortico-basal ganglia circuits in the human brain that regulate critical aspects of language, cognition, and motor control. - With Happyhour, Everyone's Under the Table
Palfreyman MT - Cell 137(5):802-804 (2009)
The molecular and cellular targets that mediate alcohol intoxication are poorly understood. In this issue, Corl et al. (2009) now implicate a new Ste20 family kinase (Happyhour) and the EGFR/ERK signaling pathway it antagonizes in alcohol intoxication in flies. - NPR1 in Plant Defense: It's Not over 'til It's Turned over
Mukhtar MS Nishimura MT Dangl J - Cell 137(5):804-806 (2009)
NPR1 is a key transcriptional coregulator in plant defense responses. In this issue, Spoel et al. (2009) demonstrate that proteasome-mediated degradation of NPR1 in the nucleus promotes efficient expression of defense response genes following infection and prevents spurious activation of defensive responses in the absence of infection. - At Loose Ends: Resecting a Double-Strand Break
Bernstein KA Rothstein R - Cell 137(5):807-810 (2009)
Double-strand break (DSB) repair is critical for maintaining genomic integrity and requires the processing of the 5′ DSB ends. Recent studies have shed light on the mechanism and regulation of DNA end processing during DSB repair by homologous recombination. - The Tortoise and the Hair: Slow-Cycling Cells in the Stem Cell Race
Fuchs E - Cell 137(5):811-819 (2009)
Given the importance of stem cells to adult tissues, it has long been postulated that stem cells divide infrequently to preserve their long-term proliferation potential and to prevent the acquisition of errors during DNA replication. Yet, some stem cells must be able to continually churn out progeny in tissues that rapidly turn over or are subject to sudden injuries or growth spurts. This Review explores the challenges that mammalian stem cells face in balancing the competing demands of proliferation and differentiation in tissues. - Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells
Scholl C Fröhling S Dunn IF Schinzel AC Barbie DA Kim SY Silver SJ Tamayo P Wadlow RC Ramaswamy S Döhner K Bullinger L Sandy P Boehm JS Root DE Jacks T Hahn WC Gilliland DG - Cell 137(5):821-834 (2009)
An alternative to therapeutic targeting of oncogenes is to perform "synthetic lethality" screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional depen dencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable" genetic alterations. - A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene
Luo J Emanuele MJ Li D Creighton CJ Schlabach MR Westbrook TF Wong KK Elledge SJ - Cell 137(5):835-848 (2009)
Oncogenic mutations in the small GTPase Ras are highly prevalent in cancer, but an understanding of the vulnerabilities of these cancers is lacking. We undertook a genome-wide RNAi screen to identify synthetic lethal interactions with the KRAS oncogene. We discovered a diverse set of proteins whose depletion selectively impaired the viability of Ras mutant cells. Among these we observed a strong enrichment for genes with mitotic functions. We describe a pathway involving the mitotic kinase PLK1, the anaphase-promoting complex/cyclosome, and the proteasome that, when inhibited, results in prometaphase accumulation and the subsequent death of Ras mutant cells. Gene expression analysis indicates that reduced expression of genes in this pathway correlates with increased survival of patients bearing tumors with a Ras transcriptional signature. Our results suggest a previously underappreciated role for Ras in mitotic progression and demonstrate a pharmacologically tractable p athway for the potential treatment of cancers harboring Ras mutations. - Mechanistic Basis of 5′-3′ Translocation in SF1B Helicases
Saikrishnan K Powell B Cook NJ Webb MR Wigley DB - Cell 137(5):849-859 (2009)
Superfamily 1B (SF1B) helicases translocate in a 5′-3′ direction and are required for a range of cellular activities across all domains of life. However, structural analyses to date have focused on how SF1A helicases achieve 3′-5′ movement along nucleic acids. We present crystal structures of the complex between the SF1B helicase RecD2 from Deinococcus radiodurans and ssDNA in the presence and absence of an ATP analog. These snapshots of the reaction pathway reveal a nucleotide binding-induced conformational change of the two motor domains that is broadly reminiscent of changes observed in other SF1 and SF2 helicases. Together with biochemical data, the structures point to a step size for translocation of one base per ATP hydrolyzed. Moreover, the structures also reveal a mechanism for nucleic acid translocation in the 5′-3′ direction by SF1B helicases that is surprisingly different from that of 3′-5′ translocation by SF1A enzymes, and explains the molec ular basis of directionality. - Proteasome-Mediated Turnover of the Transcription Coactivator NPR1 Plays Dual Roles in Regulating Plant Immunity
Spoel SH Mou Z Tada Y Spivey NW Genschik P Dong X - Cell 137(5):860-872 (2009)
Systemic acquired resistance (SAR) is a broad-spectrum plant immune response involving profound transcriptional changes that are regulated by the coactivator NPR1. Nuclear translocation of NPR1 is a critical regulatory step, but how the protein is regulated in the nucleus is unknown. Here, we show that turnover of nuclear NPR1 protein plays an important role in modulating transcription of its target genes. In the absence of pathogen challenge, NPR1 is continuously cleared from the nucleus by the proteasome, which restricts its coactivator activity to prevent untimely activation of SAR. Surprisingly, inducers of SAR promote NPR1 phosphorylation at residues Ser11/Ser15, and then facilitate its recruitment to a Cullin3-based ubiquitin ligase. Turnover of phosphorylated NPR1 is required for full induction of target genes and establishment of SAR. These in vivo data demonstrate dual roles for coactivator turnover in both preventing and stimulating gene transcription to regul ate plant immunity. - DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival
Peterson TR Laplante M Thoreen CC Sancak Y Kang SA Kuehl WM Gray NS Sabatini DM - Cell 137(5):873-886 (2009)
The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for acti vating PI3K/Akt signaling and promoting cell survival. - Multiple Assembly Chaperones Govern Biogenesis of the Proteasome Regulatory Particle Base
Funakoshi M Tomko RJ Kobayashi H Hochstrasser M - Cell 137(5):887-899 (2009)
The central protease of eukaryotes, the 26S proteasome, has a 20S proteolytic core particle (CP) and an attached 19S regulatory particle (RP). The RP is further subdivided into lid and base subcomplexes. Little is known about RP assembly. Here, we show that four conserved assembly factors govern biogenesis of the yeast RP base. Nas2 forms a complex with the Rpt4 and Rpt5 ATPases and enhances 26S proteasome formation in vivo and in vitro. Other RP subcomplexes contain Hsm3, which is related to mammalian proteasome subunit S5b. Hsm3 also contributes to base assembly. Larger Hsm3-containing complexes include two additional proteins, Nas6 and Rpn14, which function as assembly chaperones as well. Specific deletion combinations affecting these four factors cause severe perturbations to RP assembly. Our results demonstrate that proteasomal RP biogenesis requires multiple, functionally overlapping chaperones and suggest a model in which subunits form specific subcomplexes that then assemble into the base. - Multiple Proteasome-Interacting Proteins Assist the Assembly of the Yeast 19S Regulatory Particle
Saeki Y Toh-E A Kudo T Kawamura H Tanaka K - Cell 137(5):900-913 (2009)
The 26S proteasome is a highly conserved multisubunit protease that degrades ubiquitinated proteins in eukaryotic cells. The 26S proteasome consists of the proteolytic core particle (CP) and one or two 19S regulatory particles (RPs). Although the mechanisms of CP assembly are well described, the mechanism of RP assembly is largely unknown. Here, we show that four proteasome-interacting proteins (PIPs), Nas2/p27, Nas6/gankyrin, Rpn14/PAAF1, and Hsm3/S5b, bind specific Rpt subunits of the RP and interact each other genetically. Lack of these PIPs resulted in defective assembly of the 26S proteasome at an early stage, suggesting that these proteins are bona fide RP chaperones. Each of the RP chaperones formed distinct specific subassemblies of the base components and escorted them to mature RPs. Our results indicate that the RP assembly is a highly organized and elaborate process orchestrated by multiple proteasome-dedicated chaperones. - Assembly Pathway of the Mammalian Proteasome Base Subcomplex Is Mediated by Multiple Specific Chaperones
Kaneko T Hamazaki J Iemura S Sasaki K Furuyama K Natsume T Tanaka K Murata S - Cell 137(5):914-925 (2009)
The 26S proteasome is an enzymatic complex that degrades ubiquitinated proteins in eukaryotic cells. It is composed of the 20S core particle (CP) and the 19S regulatory particle (RP). The latter is further divided into the lid and base subcomplexes. While the mechanism involved in the assembly of the CP is well investigated, that of the RP is poorly understood. Here, we show that the formation of the mammalian base subcomplex involves three distinct modules, where specific pairs of ATPase subunits are associated with the distinct chaperones p28, S5b, or p27. The process of base formation starts from association of the p28-Rpt3-Rpt6-Rpn14 complex with the S5b-Rpt1-Rpt2-Rpn1 complex, followed by incorporation of the p27-Rpt5-Rpt4 complex and Rpn2, where p28, S5b, and p27 regulate the associations between the modules. These chaperones dissociate before completion of 26S proteasome formation. Our results demonstrate that base assembly is facilitated by multiple proteasome-d edicated chaperones, like CP assembly. - Structural Memory in the Contractile Ring Makes the Duration of Cytokinesis Independent of Cell Size
Carvalho A Desai A Oegema K - Cell 137(5):926-937 (2009)
Cytokinesis is accomplished by constriction of a cortical contractile ring. We show that during the early embryonic divisions in C. elegans, ring constriction occurs in two phases—an initial phase at a constant rate followed by a second phase during which the constriction rate decreases in proportion to ring perimeter. Cytokinesis completes in the same amount of time, despite the reduction in cell size during successive divisions, due to a strict proportionality between initial ring size and the constant constriction rate. During closure, the myosin motor in the ring decreases in proportion to perimeter without turning over. We propose a "contractile unit" model to explain how the ring retains a structural memory of its initial size as it disassembles. The scalability of constriction may facilitate coordination of mitotic events and cytokinesis when cell size, and hence the distance traversed by the ring, varies during embryogenesis and in other contexts. - RhoBTB3: A Rho GTPase-Family ATPase Required for Endosome to Golgi Transport
Espinosa EJ Calero M Sridevi K Pfeffer SR - Cell 137(5):938-948 (2009)
Rho GTPases are key regulators of the actin-based cytoskeleton; Rab GTPases are key regulators of membrane traffic. We report here that the atypical Rho GTPase family member, RhoBTB3, binds directly to Rab9 GTPase and functions with Rab9 in protein transport from endosomes to the trans Golgi network. Gene replacement experiments show that RhoBTB3 function in cultured cells requires both RhoBTB3′s N-terminal, Rho-related domain and C-terminal sequences that are important for Rab9 interaction. Biochemical analysis reveals that RhoBTB3 binds and hydrolyzes ATP rather than GTP. Rab9 binding opens the autoinhibited RhoBTB3 protein to permit maximal ATP hydrolysis. Because RhoBTB3 interacts with TIP47 on membranes, we propose that it may function to release this cargo selection protein from vesicles to permit their efficient docking and fusion at the Golgi. - Happyhour, a Ste20 Family Kinase, Implicates EGFR Signaling in Ethanol-Induced Behaviors
Corl AB Berger KH Ophir-Shohat G Gesch J Simms JA Bartlett SE Heberlein U - Cell 137(5):949-960 (2009)
The consequences of alcohol use disorders (AUDs) are devastating to individuals and society, yet few treatments are currently available. To identify genes regulating the behavioral effects of ethanol, we conducted a genetic screen in Drosophila and identified a mutant, happyhour (hppy), due to its increased resistance to the sedative effects of ethanol. Hppy protein shows strong homology to mammalian Ste20 family kinases of the GCK-1 subfamily. Genetic and biochemical experiments revealed that the epidermal growth factor (EGF)-signaling pathway regulates ethanol sensitivity in Drosophila and that Hppy functions as an inhibitor of the pathway. Acute pharmacological inhibition of the EGF receptor (EGFR) in adult animals altered acute ethanol sensitivity in both flies and mice and reduced ethanol consumption in a preclinical rat model of alcoholism. Inhibitors of the EGFR or components of its signaling pathway are thus potential pharmacotherapies for AUDs. - A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice
Enard W Gehre S Hammerschmidt K Hölter SM Blass T Somel M Brückner MK Schreiweis C Winter C Sohr R Becker L Wiebe V Nickel B Giger T Müller U Groszer M Adler T Aguilar A Bolle I Calzada-Wack J Dalke C Ehrhardt N Favor J Fuchs H Gailus-Durner V Hans W Hölzlwimmer G Javaheri A Kalaydjiev S Kallnik M Kling E Kunder S Mossbrugger I Naton B Racz I Rathkolb B Rozman J Schrewe A Busch DH Graw J Ivandic B Klingenspor M Klopstock T Ollert M Quintanilla-Martinez L Schulz H Wolf E Wurst W Zimmer A Fisher SE Morgenstern R Arendt T de Angelis MH Fischer J Schwarz J Pääbo S - Cell 137(5):961-971 (2009)
It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data. - Mechanism of Replication-Coupled DNA Interstrand Crosslink Repair
- Cell 137(5):972 (2009)
- SnapShot: B7/CD28 Costimulation
Paterson AM Vanguri VK Sharpe AH - Cell 137(5):974-974.e1 (2009)
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