Hot off the presses! Jan 22 Cell

The Jan 22 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 140(2):163, 165 (2010)
  
• Molecular Medicine Select
  - Cell 140(2):167, 169 (2010)
  From Alzheimer's disease and the obesity epidemic to the chronic health effects of certain viral infections, scientists in academia and big pharma are seeking new therapeutic targets and strategies to tackle these diseases. However, as discussed in this Molecular Medicine Select, designing more effective drugs with fewer side effects that fight the disease itself and not just the symptoms requires a thorough understanding of the underlying mechanisms of disease pathogenesis.
• Blocking the Deadly Effects of the NMDA Receptor in Stroke
  - Cell 140(2):174-176 (2010)
  Excessive activation of NMDA glutamate receptors contributes to neuronal death after stroke. In this issue, Tu et al. (2010) demonstrate that ischemic injury promotes the association of death-associated protein kinase 1 with the NMDA receptor, thereby potentiating its activity, and show that disrupting this association reduces damage to the brain.
• Forever Young
  - Cell 140(2):176-178 (2010)
  Propagation of a species requires periodic cell renewal to avoid clonal senescence. Liu et al. (2010) now describe a new mechanism of cell renewal in budding yeast, in which damaged protein aggregates are transported out of the daughter buds along actin cables to preserve youthfulness.
• Duct Tape for Broken Chromosomes
  - Cell 140(2):178-180 (2010)
  A cell undergoing mitosis is presented with a potentially catastrophic situation when a DNA double-strand break creates a chromosome fragment that lacks connection to a centromere. Royou et al. (2010) now reveal that this cellular crisis is averted in fruit fly neuroblasts by thin chromatin tethers that hold on to the ends of the broken chromosomes.
• The Brothers RAF
  - Cell 140(2):180-182 (2010)
  Targeted molecular therapies for cancer treatment have shown promise, but also have limitations. In this issue, Heidorn et al. (2010) find that a class of targeted molecular therapies with clinical effectiveness against one melanoma subtype may have adverse clinical effects in another.
• Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression
  - Cell 140(2):197-208 (2010)
  Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.
• DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke
  - Cell 140(2):222-234 (2010)
  N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extrasynaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at ! extrasynaptic sites and this interaction acts as a central mediator for stroke damage.
• The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates
  - Cell 140(2):257-267 (2010)
  The paradigm sirtuin, Sir2p, of budding yeast is required for establishing cellular age asymmetry, which includes the retention of damaged and aggregated proteins in mother cells. By establishing the global genetic interaction network of SIR2 we identified the polarisome, the formin Bni1p, and myosin motor protein Myo2p as essential components of the machinery segregating protein aggregates during mitotic cytokinesis. Moreover, we found that daughter cells can clear themselves of damage by a polarisome- and tropomyosin-dependent polarized flow of aggregates into the mother cell compartment. The role of Sir2p in cytoskeletal functions and polarity is linked to the CCT chaperonin in sir2Δ cells being compromised in folding actin. We discuss the findings in view of recent models hypothesizing that polarity may have evolved to avoid clonal senescence by establishing an aging (soma-like) and rejuvenated (germ-like) lineage. PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (25118 K)
• Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development
  - Cell 140(2):268-279 (2010)
  It is established that tumor cell-derived VEGF acts on endothelial cells to promote angiogenesis and tumor growth. Here, we demonstrate that in K5-SOS-dependent mouse skin tumors, autocrine VEGF is required for tumor cell proliferation in a cell-autonomous and angiogenesis-independent manner. VEGF is upregulated in SOS-expressing tumors, and its deletion in epidermal cells delays tumorigenesis by suppressing angiogenesis and tumor cell proliferation. Epidermis-specific Flt1 deletion also impairs tumorigenesis and proliferation. Surprisingly, complete tumor inhibition occurs in the absence of VEGF in EGFR mutant mice, demonstrating that VEGFR and EGFR synergize in neoplastic cells to promote tumor growth. Mechanistically, K5-SOS upregulates VEGF, Flt1, and Neuropilin-1 in an Erk-dependent manner, thereby activating an autocrine proliferation loop, whereas EGFR prevents tumor cells from apoptosis. Moreover, Flt1 is upregulated in human SCC, and its inhibition in SCC cell! s impairs proliferation. Thus, in addition to regulating angiogenesis, VEGF has to be considered as a potent growth factor for epidermal tumors.
• The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α
  - Cell 140(2):280-293 (2010)
  SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcription factor Hif1α, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1α activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and o! besity.
• SnapShot: Bacterial Appendages II
  - Cell 140(2):294-294.e1 (2010)