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Jun dimerization protein 2 controls hypoxia-induced replicative senescence via both the p16Ink4a-pRb and Arf-p53
Koji Nakade1, Chang-Shen Lin2,3, Xiao-Yu Chen4
1Gene Engineering Division RIKEN BioResource Center Tsukuba Japan.
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.
Insights
Jun dimerization protein 2 (JDP2) induces cell cycle arrest by upregulating p16Ink4a and Arf in response to oxidative stress. This involves both p16Ink4a-pRb and Arf-p53 pathways, impacting replicative senescence.
Area of Science:
- Cellular senescence
- Molecular biology
- Epigenetics
Background:
- Replicative senescence is regulated by p16Ink4a and Arf, key cell cycle inhibitors.
- Jun dimerization protein 2 (JDP2) deficiency confers resistance to senescence by altering p16Ink4a chromatin signaling.
- The role of JDP2 in oxidative stress-induced senescence via p16Ink4a-pRb or Arf-p53 pathways is unclear.
Purpose of the Study:
- To investigate the role of JDP2 in regulating p16Ink4a and Arf expression under oxidative stress.
- To determine the involvement of p16Ink4a-pRb and Arf-p53 pathways in JDP2-mediated growth suppression.
Main Methods:
- Introduction of JDP2 into mouse embryonic fibroblasts.
- Manipulation of oxygen levels (20% vs. 3% O2) to induce oxidative stress.
- Analysis of cell proliferation, p16Ink4a and Arf expression, and p53/pRb pathway activation.
Main Results:
- JDP2 introduction upregulated p16Ink4a and Arf and decreased proliferation under 20% O2, but not 3% O2.
- JDP2-mediated growth suppression was dependent on both p16Ink4a and Arf.
- Both p16Ink4a-pRb and Arf-p53 pathways, but not individually, were required to block JDP2-dependent growth inhibition.
Conclusions:
- JDP2 mediates oxidative stress signals to induce p16Ink4a and Arf.
- JDP2-induced cell cycle arrest occurs through coordinated activation of the p16Ink4a-pRb and Arf-p53 pathways.
- JDP2 plays a critical role in oxidative stress-induced replicative senescence.
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