PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts
PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts
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DOI：
10.1242/jcs.026633
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发表时间：
2008-07-01
影响因子：
4
通讯作者：
Tong, Tanjun
中科院分区：
文献类型：
--
作者：
Gan, Qini;Huang, Jing;Tong, Tanjun
过氧化物酶体增殖物激活受体γ（PPAR γ）通过促进细胞周期停滞在抑制细胞生长中起重要作用，并且PPAR γ激活诱导p16（INK 4 α）（CDKN 2A）的表达，p16（INK 4 α）（CDKN 2A）是一种可诱导衰老的重要细胞周期抑制剂。然而，PPAR-gamma在细胞衰老中的作用尚不清楚。在这里，我们表明，过氧化物酶体增殖物激活物受体γ促进细胞衰老诱导p16（INK 4 α）的表达。我们发现了几个迹象表明，PPAR γ加速细胞衰老，包括增强衰老相关（SA）-β-半乳糖苷酶染色，增加G1期阻滞和人类成纤维细胞的细胞生长延迟。Western blotting研究表明，PPAR γ激活可上调p16（INK 4 α）的表达。PPARgamma可以与p16启动子结合并诱导其转录，并且，在用选择性PPARgamma激动剂处理后，我们观察到衰老细胞中p16（INK 4 α）的表达比年轻细胞中更稳健。此外，我们的数据表明，磷酸化的过氧化物酶体增殖物激活物受体γ减少增加细胞传代。我们的研究结果提供了一个可能的分子机制的细胞衰老的调控。
Peroxisome proliferator-activated receptor gamma ( PPAR gamma) plays an important role in the inhibition of cell growth by promoting cell-cycle arrest, and PPAR gamma activation induces the expression of p16(INK4 alpha) ( CDKN2A), an important cell-cycle inhibitor that can induce senescence. However, the role of PPAR gamma in cellular senescence is unknown. Here, we show that PPAR gamma promotes cellular senescence by inducing p16(INK4 alpha) expression. We found several indications that PPAR gamma 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 PPAR gamma activation can upregulate the expression of p16(INK4 alpha). PPAR gamma can bind to the p16 promoter and induce its transcription, and, after treatment with a selective PPAR gamma agonist, we observed more-robust expression of p16(INK4 alpha) in senescent cells than in young cells. In addition, our data indicate that phosphorylation of PPAR gamma decreased with increased cell passage. Our results provide a possible molecular mechanism underlying the regulation of cellular senescence.