4.8 Article

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16INK4a

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.0600069103

Keywords

aging; cellular senescence; epigenetics; signaling networks; stress response

Funding

  1. NCRR NIH HHS [P20 RR15578, P20 RR015578] Funding Source: Medline
  2. NIA NIH HHS [R01 AG016694, R01 AG16694] Funding Source: Medline
  3. NIGMS NIH HHS [R01 GM41690, R01 GM041690] Funding Source: Medline

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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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