ATR Controls the UV-Related Upregulation of the CDKN1A mRNA in a Cdk1/HuR-Dependent Manner
ATR Controls the UV-Related Upregulation of the CDKN1A mRNA in a Cdk1/HuR-Dependent Manner
复制标题
DOI：
10.1002/mc.22066
复制
发表时间：
2014-12-01
影响因子：
4.6
通讯作者：
Aboussekhra, Abdelilah
中科院分区：
文献类型：
--
作者：
Al-Khalaf, Huda H.;Aboussekhra, Abdelilah
紫外线(UV)是一种致癌物质，可上调参与各种细胞过程的几个基因的表达，包括细胞周期检查点和细胞凋亡。通用的细胞周期蛋白依赖性激酶抑制因子p21(WAF1/Cip1)在这些过程中起着重要作用，其相应的信息水平在紫外线诱导的DNA损伤中增加了数倍。这种上调主要是由于HUR依赖的mRNA稳定而转录后的。由于蛋白激酶ATR在细胞对紫外线损伤的反应中起主要作用，我们试图探讨其在稳定编码p21(WAF1/Cip1)mRNA方面的可能意义。我们已经证明，CDKN1AmRNA的紫外线依赖积累确实是在ATR蛋白激酶的控制下。在紫外线损伤时，ATR允许HUR蛋白在核质中穿梭，从而结合CDKN1AmRNA，减少其周转。这种ATR依赖的效应是通过ATR对CDK1蛋白激酶进行紫外线相关的磷酸化/失活，从而导致Hur从CDK1中解离而实现的。事实上，在ATR缺陷细胞中抑制CDK1或shRNA特异性敲除CDK1提高了Hur的细胞质水平，并恢复了CDKN1a mRNA的上调，以应对紫外线损伤。这些结果表明，ATR通过与CDK1相关的胞质内Hur的积累来稳定CDKN1A信号对紫外线损伤的响应。(C)2013年威利期刊公司。
Ultraviolet (UV) light is a carcinogenic agent that upregulates the expression of several genes involved in various cellular processes, including cell cycle checkpoints and apoptosis. The universal cyclin-dependent kinase inhibitor p21(WAF1/Cip1) plays major roles in these processes, and the level of its corresponding message increases several times in response to UV-induced DNA damage. This upregulation is mainly posttranscriptional owing to HuR-dependent mRNA stabilization. Since the protein kinase Atr plays major roles during the cellular response to UV damage, we sought to investigate its possible implication in the stabilization of the p21(WAF1/Cip1) coding mRNA. We have shown that the UV-dependent accumulation of the CDKN1A mRNA is indeed under the control of the Atr protein kinase. Upon UV damage, Atr allows nuclear-cytoplasmic shuttling of the HuR protein, which binds the CDKN1A mRNA and reduces its turnover. This ATR-dependent effect is mediated through UV-related phosphorylation/inactivation of the Cdk1 protein kinase by Atr, which leads to the dissociation of HuR from Cdk1. Indeed, inhibition or shRNA specific knockdown of CDK1 in ATR-deficient cells enhanced the cytoplasmic level of HuR and restored the CDKN1A mRNA upregulation in response to UV damage. These results show that ATR stabilizes the CDKN1A message in response to UV damage through Cdk1-related cytoplasmic accumulation of HuR. (c) 2013 Wiley Periodicals, Inc.