ATR controls the p21WAF1/Cip1 protein up-regulation and apoptosis in response to low UV fluences
ATR controls the p21WAF1/Cip1 protein up-regulation and apoptosis in response to low UV fluences
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DOI：
10.1002/mc.20864
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发表时间：
2012-12-01
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.;Hendrayani, Siti-Faujiah;Aboussekhra, Abdelilah
通用细胞周期蛋白依赖性激酶抑制剂 p21(WAF1/Cip1) 可促进细胞周期停滞并抑制细胞凋亡，以响应紫外线诱导的 DNA 损伤。由于蛋白激酶 ATR 在细胞对这些致癌病变的反应中发挥着重要作用，我们研究了 ATR 在调节 p21(WAF1/Cip1) 表达响应 UVC 辐射中的可能作用。我们已经证明 p21(WAF1/Cip1) 在人成纤维细胞和上皮细胞中上调，但仅对低紫外线能量密度和低传代细胞有反应。重要的是，这种上调依赖于 ATR。事实上，在 ATR 缺陷或咖啡因处理的细胞中，紫外线通过 SKP2 依赖性泛素化和蛋白酶体途径降解，反而下调了 p21(WAF1/Cip1) 蛋白。此外，我们提供的证据表明，ATR 通过抑制 caspase 3 和 PARP 的裂解以及促凋亡蛋白 BAX 和 BAK 的抑制，抑制紫外线低能量密度下的细胞凋亡。有趣的是，在没有基因毒性应激的情况下，ATR 也是 p21(WAF1/Cip1) 蛋白稳定性所必需的。总之，这些结果表明，在细胞对低 UVC 影响的反应过程中，ATR 蛋白激酶上调 p21(WAF1/Cip1) 并抑制细胞凋亡。 (c) 2011 年 Wiley 期刊公司。
The universal cyclin-dependent kinase inhibitor p21(WAF1/Cip1) promotes cell cycle arrest and inhibits apoptosis in response to UV-induced DNA damage. Since the protein kinase ATR plays a major role in the cellular response to these carcinogenic lesions, we investigated the possible role of ATR in the modulation of p21(WAF1/Cip1) expression in response to UVC radiation. We have shown that p21(WAF1/Cip1) is up-regulated in human fibroblast and epithelial cells, but only in response to low UV fluences and low passage cells. Importantly, this up-regulation is ATR-dependent. In fact, in ATR-deficient or caffeine-treated cells UV light rather down-regulated the p21(WAF1/Cip1) protein through SKP2-dependent ubiquitination and degradation via the proteasomal pathway. Furthermore, we present evidence that ATR inhibits apoptosis in response to low fluences of UV light, through inhibiting the cleavage of caspase 3 and PARP as well as the repression of the proapoptotic proteins BAX and BAK. Interestingly, ATR is also required for the stability of the p21(WAF1/Cip1) protein in absence of genotoxic stress. Together, these results indicate that during the cellular response to low UVC fluences the ATR protein kinase up-regulates p21(WAF1/Cip1) and inhibits apoptosis. (c) 2011 Wiley Periodicals, Inc.