The p16INK4a tumor suppressor controls p21WAF1 induction in response to ultraviolet light
The p16INK4a tumor suppressor controls p21WAF1 induction in response to ultraviolet light
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DOI：
10.1093/nar/gkl1075
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发表时间：
2007-01-01
影响因子：
14.9
通讯作者：
Aboussekhra, Abdelilah
中科院分区：
文献类型：
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作者：
Al-Mohanna, Mai A.;Al-Khalaf, Huda H.;Aboussekhra, Abdelilah
p16（INK4a）和p21（WAF1）是两种主要的细胞周期蛋白依赖性激酶抑制剂，是两种肿瘤抑制基因的产物，在多种细胞代谢途径中发挥重要作用。p21（WAF 1）响应于不同的DNA损伤剂而上调。虽然p21（WAF 1）的激活是p53依赖性的γ射线后，紫外线（UV）光对p21（WAF 1）蛋白水平的影响仍不清楚。在本报告中，我们表明，p21（WAF 1）蛋白的水平增加，在不同的哺乳动物细胞中响应低UVC通量。这种上调是通过在人和小鼠细胞中以p16（INK4a）依赖性方式稳定p21（WAF 1）mRNA介导的。此外，使用p16-siRNA处理的人皮肤成纤维细胞，我们已经表明，p16控制的mRNA结合HuR蛋白的UV依赖性细胞质积累。此外，HuR免疫沉淀显示，HuR与p21 mRNA的UV依赖性结合与p16相关。这表明p16通过使HuR从细胞核重新定位到细胞质来诱导p21。因此，我们还表明，p16是必要的有效的紫外线依赖性p53上调，这也需要HuR。这些结果表明，除了其在细胞增殖中的作用，p16（INK4a）也是细胞对UV损伤反应的重要调节因子。
p16(INK4a) and p21(WAF1), two major cyclin-dependent kinase inhibitors, are the products of two tumor suppressor genes that play important roles in various cellular metabolic pathways. p21(WAF1) is up-regulated in response to different DNA damaging agents. While the activation of p21(WAF1) is p53-dependent following gamma-rays, the effect of ultraviolet (UV) light on p21(WAF1) protein level is still unclear. In the present report, we show that the level of the p21(WAF1) protein augments in response to low UVC fluences in different mammalian cells. This up-regulation is mediated through the stabilization of p21(WAF1) mRNA in a p16(INK4a)-dependent manner in both human and mouse cells. Furthermore, using p16-siRNA treated human skin fibroblast; we have shown that p16 controls the UV-dependent cytoplasmic accumulation of the mRNA binding HuR protein. In addition, HuR immunoprecipitations showed that UV-dependent binding of HuR to p21 mRNA is p16-related. This suggests that p16 induces p21 by enabling the relocalization of HuR from the nucleus to the cytoplasm. Accordingly, we have also shown that p16 is necessary for efficient UV-dependent p53 up-regulation, which also requires HuR. These results indicate that, in addition to its role in cell proliferation, p16(INK4a) is also an important regulator of the cellular response to UV damage.