Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin
Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin
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DOI：
10.1074/jbc.m004267200
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发表时间：
2000-11-17
影响因子：
4.8
通讯作者：
Pelling, JC
中科院分区：
文献类型：
--
作者：
Persons, DL;Yazlovitskaya, EM;Pelling, JC
p53肿瘤抑制蛋白是在DNA损伤反应中起主要作用的转录因子。DNA损伤后，p53水平增加主要是由于蛋白质的稳定。导致DNA损伤后p53稳定的分子机制尚未完全阐明。最近，我们报道了顺铂治疗激活细胞外信号调节激酶1和2（ERK 1/2），抑制ERK 1/2导致顺铂敏感性增强。在本研究中，我们研究了ERK 1/2激活在调节顺铂对p53反应中的潜在作用。在卵巢癌细胞系A2780中，用丝裂原活化蛋白激酶/ERK激酶1（MEK 1）抑制剂PD 98059抑制ERK 1/2活化导致顺铂暴露期间p53蛋白半衰期缩短和p53蛋白蓄积减少。我们还证明了p53蛋白与ERK 1/2蛋白共免疫沉淀，并在体外被活化的重组小鼠ERK 2磷酸化。此外，PD 98059降低了顺铂暴露期间p53在丝氨酸15处的磷酸化，表明ERK 1/2在顺铂DNA反应期间部分介导p53的磷酸化。这些结果强烈表明，顺铂诱导的ERK激活是一个上游调节剂的p53对顺铂引起的DNA损伤的反应。
The p53 tumor suppressor protein is a transcription factor that plays a major role in the DNA damage response. After DNA damage, p53 levels increase due primarily to stabilization of the protein. The molecular mechanisms leading to stabilization of p53 after DNA damage have not been completely elucidated. Recently we reported that cisplatin treatment activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and that inhibition of ERK1/2 resulted in enhanced sensitivity to cisplatin. In the present study, we examined the potential role of ERK1/2 activation in regulation of the p53 response to cisplatin. In the ovarian carcinoma cell line A2780, inhibition of ERK1/2 activation with the mitogen-activated protein kinase/ERK kinase 1 (MEK1) inhibitor PD98059 resulted in decreased p53 protein half-life and diminished accumulation of p53 protein during exposure to cisplatin. We also demonstrated that p53 protein co-immunoprecipitated with ERK1/2 protein and was phosphorylated by activated recombinant murine ERK2 in vitro. Furthermore, PD98059 decreased the phosphorylation of p53 at serine 15 during cisplatin exposure, suggesting that ERK1/2 mediates in part phosphorylation of p53 during the cisplatin DNA response. These results strongly suggest that cisplatin-induced ERK activation is an up-stream regulator of the p53 response to DNA damage caused by cisplatin.