Department of Cell Stress Biology; Roswell Park Cancer Institute; Elm & Carlton Streets; Buffalo, NY USA.
Cell Cycle. 2013 Sep 15;12(18):3063-9. doi: 10.4161/cc.26130. Epub 2013 Aug 22.
CDKN1A (p21) and CDKN2A (p16) inhibit CDK4/6, initiating senescence. According to our view on senescence, the role of p21 and p16 is to cause cell cycle arrest, whereas MTOR (mechanistic target of rapamycin) drives geroconversion to senescence. Recently we demonstrated that one of the markers of p21- and p16-initiated senescence is MEK-dependent hyper-elevation of cyclin D1. We noticed that a synthetic inhibitor of CDK 4/6 (PD0332991) also induced cyclin D1-positive senescence. We demonstrated that PD0332991 and p21 caused almost identical senescence phenotypes. p21, p16, and PD0332991 do not inhibit MTOR, and rapamycin decelerates geroconversion caused by all 3 molecules. Like p21, PD0332991 initiated senescence at any concentration that inhibited cell proliferation. This confirms the notion that a mere arrest in the presence of active MTOR may lead to senescence.
CDKN1A（p21）和 CDKN2A（p16）抑制 CDK4/6，引发衰老。根据我们对衰老的理解，p21 和 p16 的作用是引起细胞周期停滞，而 MTOR（雷帕霉素的作用靶点）驱动衰老向 geroconversion 的转化。最近我们证明，p21 和 p16 引发的衰老的一个标志是 MEK 依赖性 cyclin D1 的过度升高。我们注意到，一种 CDK4/6 的合成抑制剂（PD0332991）也诱导 cyclin D1 阳性衰老。我们证明 PD0332991 和 p21 引起几乎相同的衰老表型。p21、p16 和 PD0332991 均不抑制 MTOR，雷帕霉素可减缓这 3 种分子引起的 geroconversion。与 p21 一样，PD0332991 在抑制细胞增殖的任何浓度下都能引发衰老。这证实了这样一种观点，即在存在活跃的 MTOR 的情况下仅仅是细胞周期停滞就可能导致衰老。
