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  • Title: Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).
    Author: Guney I, Wu S, Sedivy JM.
    Journal: Proc Natl Acad Sci U S A; 2006 Mar 07; 103(10):3645-50. PubMed ID: 16537449.
    Abstract:
    Increased mitogenic signaling by positive effectors such as Ras or Myc can trigger senescence in normal cells, a response believed to function as a tumor-suppressive mechanism. We report here the existence of a checkpoint that monitors hypoproliferative signaling imbalances. Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16(INK4a). p16(INK4a) expression was regulated by the Polycomb group repressor Bmi-1, which we show is a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a mechanism for the conversion of environmental inputs that converge on c-Myc into discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for limiting the proliferation of damaged or otherwise physiologically compromised cells would be expected to have important consequences on the generation of replicatively senescent cells during organismal aging.
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