Monday, February 28, 2011

Hot off the presses! Feb 18 Cell

The Feb 18 issue of the Cell is now up on Pubget (About Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • In This Issue
    - cell 144(4):455, 457 (2011)
  • Cell Culture: Academy Awards
    - cell 144(4):459, 461 (2011)
    On February 27, 2011, Hollywood's royalty will gather in Kodak Theater to honor the best films of 2010. To add a scientific twist on this year's Academy Awards, Cell Culture dives beneath the skin of the top films' protagonists, identifying a brain structure that impacts our "friend count," genes that make a king stammer, a cellular fragmentation process that saves a solo hiker, and stem cells required for a ballerina to grow feathers. May I have the viral envelope, please?
  • The Grand Finale
    - cell 144(4):463-464 (2011)
  • Targeting Aneuploidy for Cancer Therapy
    - cell 144(4):465-466 (2011)
    Tumor cells frequently display an abnormal number of chromosomes, a phenomenon known as aneuploidy. Tang et al. (2011) now show that aneuploid cells are particularly sensitive to compounds that induce proteotoxic and energy stress. Could this vulnerability lead to new cancer therapies?
  • IL-7 Knocks the Socs Off Chronic Viral Infection
    - cell 144(4):467-468 (2011)
    Chronic viral infections represent a major burden to human health, and modulation of the immune system is emerging as a novel approach to fighting such infections. Pellegrini et al. (2011) demonstrate that treatment with the cytokine IL-7 may reinvigorate the immune response to persistent infection by targeting immunosuppressive Socs3 proteins.
  • Microbial Communication Superhighways
    - cell 144(4):469-470 (2011)
    Exchange of information is critical for bacterial social behaviors. Now Dubey and Ben-Yehuda (2011) provide evidence for bacterial "nanotube" conduits that allow microbes to directly exchange cytoplasmic factors. Protein and DNA transfer between distantly related species raises the prospect of a new, widely distributed mechanism of bacterial communication.
  • Epigenetic Centromere Propagation and the Nature of CENP-A Nucleosomes
    - cell 144(4):471-479 (2011)
    Centromeres direct chromosome inheritance, but in multicellular organisms their positions on chromosomes are primarily specified epigenetically rather than by a DNA sequence. The major candidate for the epigenetic mark is chromatin assembled with the histone H3 variant CENP-A. Recent studies offer conflicting evidence for the structure of CENP-A-containing chromatin, including the histone composition and handedness of the DNA wrapped around the histones. We present a model for the assembly and deposition of centromeric nucleosomes that couples these processes to the cell cycle. This model reconciles divergent data for CENP-A-containing nucleosomes and provides a basis for how centromere identity is stably inherited.
  • Revisiting the Central Dogma One Molecule at a Time
    - cell 144(4):480-497 (2011)
    The faithful relay and timely expression of genetic information depend on specialized molecular machines, many of which function as nucleic acid translocases. The emergence over the last decade of single-molecule fluorescence detection and manipulation techniques with nm and Å resolution and their application to the study of nucleic acid translocases are painting an increasingly sharp picture of the inner workings of these machines, the dynamics and coordination of their moving parts, their thermodynamic efficiency, and the nature of their transient intermediates. Here we present an overview of the main results arrived at by the application of single-molecule methods to the study of the main machines of the central dogma.
  • Identification of Aneuploidy-Selective Antiproliferation Compounds
    - cell 144(4):499-512 (2011)
    Aneuploidy, an incorrect chromosome number, is a hallmark of cancer. Compounds that cause lethality in aneuploid, but not euploid, cells could therefore provide new cancer therapies. We have identified the energy stress-inducing agent AICAR, the protein folding inhibitor 17-AAG, and the autophagy inhibitor chloroquine as exhibiting this property. AICAR induces p53-mediated apoptosis in primary mouse embryonic fibroblasts (MEFs) trisomic for chromosome 1, 13, 16, or 19. AICAR and 17-AAG, especially when combined, also show efficacy against aneuploid human cancer cell lines. Our results suggest that compounds that interfere with pathways that are essential for the survival of aneuploid cells could serve as a new treatment strategy against a broad spectrum of human tumors.
  • Role for Dpy-30 in ES Cell-Fate Specification by Regulation of H3K4 Methylation within Bivalent Domains
    - cell 144(4):513-525 (2011)
    Histone H3K4 methylation is associated with active genes and, along with H3K27 methylation, is part of a bivalent chromatin mark that typifies poised developmental genes in embryonic stem cells (ESCs). However, its functional roles in ESC maintenance and differentiation are not established. Here we show that mammalian Dpy-30, a core subunit of the SET1/MLL histone methyltransferase complexes, modulates H3K4 methylation in vitro, and directly regulates chromosomal H3K4 trimethylation (H3K4me3) throughout the mammalian genome. Depletion of Dpy-30 does not affect ESC self-renewal, but significantly alters the differentiation potential of ESCs, particularly along the neural lineage. The differentiation defect is accompanied by defects in gene induction and in H3K4 methylation at key developmental loci. Our results strongly indicate an essential functional role for Dpy-30 and SET1/MLL complex-mediated H3K4 methylation, as a component of the bivalent mark, at developmental g! enes during the ESC fate transitions.
  • ATP Binds to Proteasomal ATPases in Pairs with Distinct Functional Effects, Implying an Ordered Reaction Cycle
    - cell 144(4):526-538 (2011)
    In the eukaryotic 26S proteasome, the 20S particle is regulated by six AAA ATPase subunits and, in archaea, by a homologous ring complex, PAN. To clarify the role of ATP in proteolysis, we studied how nucleotides bind to PAN. Although PAN has six identical subunits, it binds ATPs in pairs, and its subunits exhibit three conformational states with high, low, or no affinity for ATP. When PAN binds two ATPγS molecules or two ATPγS plus two ADP molecules, it is maximally active in binding protein substrates, associating with the 20S particle, and promoting 20S gate opening. However, binding of four ATPγS molecules reduces these functions. The 26S proteasome shows similar nucleotide dependence. These findings imply an ordered cyclical mechanism in which two ATPase subunits bind ATP simultaneously and dock into the 20S. These results can explain how these hexameric ATPases interact with and "wobble" on top of the heptameric 20S proteasome.
  • Phosphorylation of Nup98 by Multiple Kinases Is Crucial for NPC Disassembly during Mitotic Entry
    - cell 144(4):539-550 (2011)
    Disassembly of nuclear pore complexes (NPCs) is a decisive event during mitotic entry in cells undergoing open mitosis, yet the molecular mechanisms underlying NPC disassembly are unknown. Using chemical inhibition and depletion experiments we show that NPC disassembly is a phosphorylation-driven process, dependent on CDK1 activity and supported by members of the NIMA-related kinase (Nek) family. We identify phosphorylation of the GLFG-repeat nucleoporin Nup98 as an important step in mitotic NPC disassembly. Mitotic hyperphosphorylation of Nup98 is accomplished by multiple kinases, including CDK1 and Neks. Nuclei carrying a phosphodeficient mutant of Nup98 undergo nuclear envelope breakdown slowly, such that both the dissociation of Nup98 from NPCs and the permeabilization of the nuclear envelope are delayed. Together, our data provide evidence for a phosphorylation-dependent mechanism underlying disintegration of NPCs during prophase. Moreover, we identify mitotic pho! sphorylation of Nup98 as a rate-limiting step in mitotic NPC disassembly.
  • Stable Kinesin and Dynein Assemblies Drive the Axonal Transport of Mammalian Prion Protein Vesicles
    - cell 144(4):551-565 (2011)
    Kinesin and dynein are opposite-polarity microtubule motors that drive the tightly regulated transport of a variety of cargoes. Both motors can bind to cargo, but their overall composition on axonal vesicles and whether this composition directly modulates transport activity are unknown. Here we characterize the intracellular transport and steady-state motor subunit composition of mammalian prion protein (PrPC) vesicles. We identify Kinesin-1 and cytoplasmic dynein as major PrPC vesicle motor complexes and show that their activities are tightly coupled. Regulation of normal retrograde transport by Kinesin-1 is independent of dynein-vesicle attachment and requires the vesicle association of a complete Kinesin-1 heavy and light chain holoenzyme. Furthermore, motor subunits remain stably associated with stationary as well as with moving vesicles. Our data suggest a coordination model wherein PrPC vesicles maintain a stable population of associated motors whose activity is ! modulated by regulatory factors instead of by structural changes to motor-cargo associations.
  • DNA Damage in Oocytes Induces a Switch of the Quality Control Factor TAp63α from Dimer to Tetramer
    - cell 144(4):566-576 (2011)
    TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with 20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63α is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63α is inhibited by complex domain-domain interactions that pro! vide the basis for regulating quality control in oocytes.
  • The Basement Membrane of Hair Follicle Stem Cells Is a Muscle Cell Niche
    - cell 144(4):577-589 (2011)
    The hair follicle bulge in the epidermis associates with the arrector pili muscle (APM) that is responsible for piloerection ("goosebumps"). We show that stem cells in the bulge deposit nephronectin into the underlying basement membrane, thus regulating the adhesion of mesenchymal cells expressing the nephronectin receptor, α8β1 integrin, to the bulge. Nephronectin induces α8 integrin-positive mesenchymal cells to upregulate smooth muscle markers. In nephronectin knockout mice, fewer arrector pili muscles form in the skin, and they attach to the follicle above the bulge, where there is compensatory upregulation of the nephronectin family member EGFL6. Deletion of α8 integrin also abolishes selective APM anchorage to the bulge. Nephronectin is a Wnt target; epidermal β-catenin activation upregulates epidermal nephronectin and dermal α8 integrin expression. Thus, bulge stem cells, via nephronectin expression, create a smooth muscle cell niche and act as tendon ! cells for the APM. Our results reveal a functional role for basement membrane heterogeneity in tissue patterning. PaperClip
  • Intercellular Nanotubes Mediate Bacterial Communication
    - cell 144(4):590-600 (2011)
    Bacteria are known to communicate primarily via secreted extracellular factors. Here we identify a previously uncharacterized type of bacterial communication mediated by nanotubes that bridge neighboring cells. Using Bacillus subtilis as a model organism, we visualized transfer of cytoplasmic fluorescent molecules between adjacent cells. Additionally, by coculturing strains harboring different antibiotic resistance genes, we demonstrated that molecular exchange enables cells to transiently acquire nonhereditary resistance. Furthermore, nonconjugative plasmids could be transferred from one cell to another, thereby conferring hereditary features to recipient cells. Electron microscopy revealed the existence of variously sized tubular extensions bridging neighboring cells, serving as a route for exchange of intracellular molecules. These nanotubes also formed in an interspecies manner, between B. subtilis and Staphylococcus aureus, and even between B. subtilis and the evo! lutionary distant bacterium Escherichia coli. We propose that nanotubes represent a major form of bacterial communication in nature, providing a network for exchange of cellular molecules within and between species. PaperFlick
  • IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology
    - cell 144(4):601-613 (2011)
    Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications f! or its use as a therapeutic in the treatment of chronic viral diseases.
  • The Coding of Temperature in the Drosophila Brain
    - cell 144(4):614-624 (2011)
    Thermosensation is an indispensable sensory modality. Here, we study temperature coding in Drosophila, and show that temperature is represented by a spatial map of activity in the brain. First, we identify TRP channels that function in the fly antenna to mediate the detection of cold stimuli. Next, we identify the hot-sensing neurons and show that hot and cold antennal receptors project onto distinct, but adjacent glomeruli in the Proximal-Antennal-Protocerebrum (PAP) forming a thermotopic map in the brain. We use two-photon imaging to reveal the functional segregation of hot and cold responses in the PAP, and show that silencing the hot- or cold-sensing neurons produces animals with distinct and discrete deficits in their behavioral responses to thermal stimuli. Together, these results demonstrate that dedicated populations of cells orchestrate behavioral responses to different temperature stimuli, and reveal a labeled-line logic for the coding of temperature informat! ion in the brain.
  • SnapShot: Chromatin Remodeling: CHD
    - cell 144(4):626-626.e1 (2011)

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