Gan Qini, Huang Jing, Zhou Rui, Niu Jing, Zhu Xiaojun, Wang Jing, Zhang Zongyu, Tong Tanjun
Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, People's Republic of China.
J Cell Sci. 2008 Jul 1;121(Pt 13):2235-45. doi: 10.1242/jcs.026633. Epub 2008 Jun 10.
Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in the inhibition of cell growth by promoting cell-cycle arrest, and PPARgamma activation induces the expression of p16(INK4alpha) (CDKN2A), an important cell-cycle inhibitor that can induce senescence. However, the role of PPARgamma in cellular senescence is unknown. Here, we show that PPARgamma promotes cellular senescence by inducing p16(INK4alpha) expression. We found several indications that PPARgamma accelerates cellular senescence, including enhanced senescence-associated (SA)-beta-galactosidase staining, increased G1 arrest and delayed cell growth in human fibroblasts. Western blotting studies demonstrated that PPARgamma activation can upregulate the expression of p16(INK4alpha). PPARgamma can bind to the p16 promoter and induce its transcription, and, after treatment with a selective PPARgamma agonist, we observed more-robust expression of p16(INK4alpha) in senescent cells than in young cells. In addition, our data indicate that phosphorylation of PPARgamma decreased with increased cell passage. Our results provide a possible molecular mechanism underlying the regulation of cellular senescence.
过氧化物酶体增殖物激活受体γ（PPARγ）通过促进细胞周期停滞在抑制细胞生长中发挥重要作用，并且PPARγ激活可诱导p16（INK4α）（CDKN2A）的表达，p16（INK4α）是一种可诱导衰老的重要细胞周期抑制剂。然而，PPARγ在细胞衰老中的作用尚不清楚。在此，我们表明PPARγ通过诱导p16（INK4α）表达促进细胞衰老。我们发现了几个表明PPARγ加速细胞衰老的迹象，包括人成纤维细胞中衰老相关（SA）-β-半乳糖苷酶染色增强、G1期停滞增加和细胞生长延迟。蛋白质印迹研究表明，PPARγ激活可上调p16（INK4α）的表达。PPARγ可与p16启动子结合并诱导其转录，并且在用选择性PPARγ激动剂处理后，我们观察到衰老细胞中p16（INK4α）的表达比年轻细胞中更强烈。此外，我们的数据表明PPARγ的磷酸化随着细胞传代次数的增加而降低。我们的结果为细胞衰老调控提供了一种可能的分子机制。
