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

The main regulators of replicative senescence in mice are p16 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 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-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 and Arf and decreases cell proliferation in the presence of environmental (20% O), but not in low (3% O) oxygen. JDP2-mediated growth suppression was inhibited by the downregulation of both p16 and Arf. Conversely, the forced expression of p16 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 and Arf by mediating signals from oxidative stress, resulting in cell cycle arrest via both the p16-pRb and Arf-p53 pathways.