Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215
Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215
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DOI：
10.1074/jbc.m406802200
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发表时间：
2004-12-10
影响因子：
4.8
通讯作者：
Cheng, JQ
中科院分区：
文献类型：
--
作者：
Li, QY;Kaneko, S;Cheng, JQ
肿瘤抑制基因P53在决定是否阻止细胞周期进程或诱导细胞凋亡以响应各种刺激方面起着重要作用。P53的翻译后修饰和与其他蛋白质的结合参与了其稳定性和反式激活活性的调节。在这里，我们显示P53被丝氨酸215处的有丝分裂激酶Aurora-A磷酸化。与大多数已发现的与P53功能正相关的P53磷酸化位点不同(Brooks，C.L.和Gu，W.(2003)Curr.奥平。细胞生物。15,164-171)，Aurora-A在Ser-215处对P53的磷酸化取消了P53的DNA结合和反式激活活性。P53下游靶基因p21(Cip/WAF1)和PTEN被Aurora-A以Ser-215磷酸化依赖的方式抑制(即磷酸化的P53-S215D丢失，非磷酸化的P53-S215A保持正常的P53功能)。因此，Aurora-A分别阻断了顺铂和伽玛射线诱导的细胞凋亡和细胞周期停滞。然而，Aurora-A对P53 DNA结合和反式激活活性的影响不受Ser-315的磷酸化影响，Ser-315是最近发现的P53的Aurora-A磷酸化位点(Katayama，H.，Sasai，K.，Kawai，H.，袁，Z.M.，Bondaruk，J.，Suzuki，F.，Fujii，S.，Arlinghaus，R.B.，Czerniak，B.A.和Sen，S.(2004)NAT)。吉内。36、55-62)。我们的数据表明，Aurora-A对Ser-215上的P53的磷酸化是使P53失活的主要机制，并可以为Aurora-A的功能提供分子基础。
The tumor suppressor p53 is important in the decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. p53 post-translational modifications and association with other proteins have been implicated in the regulation of its stability and transactivation activity. Here we show that p53 is phosphorylated by the mitotic kinase Aurora-A at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (Brooks, C. L., and Gu, W. (2003) Curr. Opin. Cell Biol. 15, 164-171), the phosphorylation of p53 by Aurora-A at Ser-215 abrogates p53 DNA binding and transactivation activity. Downstream target genes of p53, such as p21(Cip/WAF1) and PTEN, were inhibited by Aurora-A in a Ser-215 phosphorylation-dependent manner (i.e. phosphomimic p53-S215D lost and non-phosphorylatable p53-S215A retained normal p53 function). As a result, Aurora-A overrides the apoptosis and cell cycle arrest induced by cisplatin and gamma-irradiation, respectively. However, the effect of Aurora-A on p53 DNA binding and transactivation activity was not affected by phosphorylation of Ser-315, a recently identified Aurora-A phosphorylation site of p53 (Katayama, H., Sasai, K., Kawai, H., Yuan, Z. M., Bondaruk, J., Suzuki, F., Fujii, S., Arlinghaus, R. B., Czerniak, B. A., and Sen, S. (2004) Nat. Genet. 36, 55-62). Our data indicate that phosphorylation of p53 at Ser-215 by Aurora-A is a major mechanism to inactivate p53 and can provide a molecular insight for Aurora-A function.