PPAR{gamma} accelerates cellular senescence by inducing p16INK4{alpha} expression in human diploid fibroblasts.

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.