p107 inhibits G1 to S phase progression by downregulating expression of the F-box protein Skp2
p107 inhibits G1 to S phase progression by downregulating expression of the F-box protein Skp2
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DOI：
10.1083/jcb.200404146
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发表时间：
2005-01-03
影响因子：
7.8
通讯作者：
Meloche, S
中科院分区：
文献类型：
--
作者：
Rodier, G;Makris, C;Meloche, S
细胞周期进程受口袋蛋白pRb、p107和p130负调控。然而，这种抑制的机制尚未完全了解。在这里，我们表明，p107在成纤维细胞中的过度表达抑制Cdk 2激活和延迟S期进入。Cdk 2活性的抑制与p27的积累相关，从而减少蛋白质的降解，而Thr 187磷酸化没有变化。相反，我们观察到在p107过表达细胞中F-box受体Skp 2的丰度显著降低。相反，Skp 2在p107（-/-）胚胎成纤维细胞中积累到更高的水平。5 kp 2的异位表达使p27下调和DNA合成恢复到亲本细胞中观察到的水平，而Skp 2的失活消除了p107对S期进入的抑制作用。我们进一步表明，在G1期进展过程中观察到的Skp 2半衰期的血清依赖性增加在过表达p107的细胞中受损。我们提出，p107，除了其与E2 F的相互作用，抑制细胞增殖通过控制Skp 2的表达和由此产生的p27的稳定。
C ell cycle progression is negatively regulated by the pocket proteins pRb, p107, and p130. However, the mechanisms responsible for this inhibition are not fully understood. Here, we show that overexpression of p107 in fibroblasts inhibits Cdk2 activation and delays S phase entry. The inhibition of Cdk2 activity is correlated with the accumulation of p27, consequent to a decreased degradation of the protein, with no change of Thr187 phosphorylation. instead, we observed a marked decrease in the abundance of the F-box receptor Skp2 in p107-overexpressing cells. Reciprocally, Skp2 accumulates to higher levels in p107(-/-) embryonic fibroblasts. Ectopic expression of 5kp2 restores p27 down-regulation and DNA synthesis to the levels observed in parental cells, whereas inactivation of Skp2 abrogates the inhibitory effect of p107 on S phase entry. We further show that the serum-dependent increase in Skp2 half-life observed during G1 progression is impaired in cells overexpressing p107. We propose that p107, in addition to its interaction with E2F, inhibits cell proliferation through the control of Skp2 expression and the resulting stabilization of p27.