AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival
AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival
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DOI：
10.1074/jbc.m109062200
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发表时间：
2002-03-29
影响因子：
4.8
通讯作者：
Lasky, LA
中科院分区：
文献类型：
--
作者：
Li, Y;Dowbenko, D;Lasky, LA
p21（Cip 1/WAF 1）（p21）是一种p53诱导的蛋白，是细胞周期和细胞存活的关键调节因子。p21结合并抑制DNA合成调节剂增殖细胞核抗原和细胞周期蛋白A/E-CDK 2复合物。最近，p21也被证明是细胞周期进程的正调节因子，因为p21对于细胞周期蛋白D1-CDK 4/6复合物的组装和活化是必需的。此外，已在各种侵袭性肿瘤中观察到升高的p21蛋白水平以及与化学抗性相关。在这里，我们证明，p21是直接磷酸化的AKT/PKB，一种生存激酶，是过度激活，在许多晚期肿瘤。P21羧基端的两个位点（Thr（145）和Ser（146））在体外和体内均被AKT/PKB磷酸化。Thr（145）磷酸化抑制PCNA结合，而Ser（146）磷酸化显著增加p21蛋白稳定性。具有活化的AKT/PKB的胶质母细胞瘤细胞系显示出增强的p21稳定性，并且它们对紫杉醇介导的毒性更具抗性。最后，AKT/PKB通过调节p21和cyclin D1水平来控制cyclin D1-CDK 4复合物的组装。这些数据表明，肿瘤中p21水平的提高部分是由于活化的AKT/PKB的磷酸化。此外，他们认为AKT/PKB调节肿瘤细胞生存和/或增殖的机制之一是稳定p21蛋白。
p21(Cip1/WAF1) (p21), a p53-inducible protein, is a critical regulator of cell cycle and cell survival. p21 binds to and inhibits both the DNA synthesis regulator proliferating cell nuclear antigen and cyclin A/E-CDK2 complexes. Recently, p21 has also been shown to be a positive regulator of cell cycle progression as p21 is necessary for the assembly and activation of cyclin D1-CDK4/6 complexes. Furthermore, elevated p21 protein levels have been observed in various aggressive tumors as well as linked to chemoresistance. Here we demonstrate that p21 is directly phosphorylated by AKT/PKB, a survival kinase that is hyperactivated in many late stage tumors. Two sites (Thr(145) and Ser(146)) in the carboxyl terminus of p21 are phosphorylated by AKT/PKB in vitro and in vivo. Phosphorylation of Thr(145) inhibits PCNA binding, whereas phosphorylation of Ser(146) significantly increases p21 protein stability. Glioblastoma cell lines with activated AKT/PKB show enhanced p21 stability, and they are more resistant to taxol-mediated toxicity. Finally, AKT/PKB controls the assembly of cyclin D1-CDK4 complexes through modulation of p21 and cyclin D1 levels. These data imply that enhanced levels of p21 in tumors are due, in part, to phosphorylation by activated AKT/PKB. Furthermore, they suggest that one mechanism of AKT/PKB regulation of tumor cell survival and/or proliferation is to stabilize p21 protein.