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Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).

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.

SUBMITTER: Guney I

PROVIDER: S-EPMC1450136 | biostudies-other | 2006 Mar

REPOSITORIES: biostudies-other

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Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction.

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