Abstract
The main regulators of replicative senescence in mice are p16Ink4a 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 p16Ink4a 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 p16Ink4a‐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 p16Ink4a 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 p16Ink4a and Arf. Conversely, the forced expression of p16Ink4a 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 p16Ink4a and Arf by mediating signals from oxidative stress, resulting in cell cycle arrest via both the p16Ink4a‐pRb and Arf‐p53 pathways.
Highlights
The main regulators of replicative senescence in mice are p16Ink4a and Arf, inhibitors of cell cycle progression
We demonstrated that the downregulation of both p53 and pRb, but not of each of them individually, suppressed Jun dimerization protein 2 (JDP2)-dependent growth inhibition. These results suggest that JDP2 mediates signals that arise from environmental oxidative stress, induces the expression of p16Ink4a and Arf, and inhibits cell cycle progression via both the p53 and pRb pathways
We found that the expression of p16Ink4a and Arf was elevated in the JDP2 transformants compared with that of the empty vector transformants cultured in 20% O2 (Fig. 1D), but not in 3% O2 (Fig. 1D)
Summary
The main regulators of replicative senescence in mice are p16Ink4a 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 p16Ink4a and inhibits the methylation of lysine 27 of the histone H3 locus. 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 p16Ink4a and Arf by mediating signals from oxidative stress, resulting in cell cycle arrest via both the p16Ink4a-pRb and Arf-p53 pathways. Replicative senescence involves processes that include the accumulation of oxidative stress, genotoxic stress, and telomere shortening These stimuli induce the expression of p16Ink4a and Arf. In the case of cultured mouse fibroblasts, cells undergo senescence even though they have long telomeres and high telomerase activity [1]. P16Ink4a and Arf inhibit cell proliferation via pRb- and p53-dependent pathways, respectively
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