Jun dimerization protein 2 controls hypoxia-induced replicative senescence via both the p16^Ink4a-pRb and Arf-p53 pathways.

ABSTRACT: The main regulators of replicative senescence in mice are p16^Ink4a and Arf, inhibitors of cell cycle progression. Jun dimerization protein 2 (JDP2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence through recruitment of the Polycomb repressive complexes 1 and 2 to the promoter of the gene that encodes p16^Ink4a and inhibits the methylation of lysine 27 of the histone H3 locus. However, whether or not JDP2 is able to regulate the chromatin signaling of either p16^Ink4a-pRb or Arf-p53, or both, in response to oxidative stress remains elusive. Thus, this study sought to clarify this point. We demonstrated that the introduction of JDP2 leads to upregulation of p16^Ink4a and Arf and decreases cell proliferation in the presence of environmental (20% O₂), but not in low (3% O₂) oxygen. JDP2-mediated growth suppression was inhibited by the downregulation of both p16^Ink4a and Arf. Conversely, the forced expression of p16^Ink4a or Arf inhibited cell growth even in the absence of JDP2. The downregulation of both the p53 and pRb pathways, but not each individually, was sufficient to block JDP2-dependent growth inhibition. These data suggest that JDP2 induces p16^Ink4a and Arf by mediating signals from oxidative stress, resulting in cell cycle arrest via both the p16^Ink4a-pRb and Arf-p53 pathways.

SUBMITTER: Nakade K 

PROVIDER: S-EPMC5666393 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature