Al-Mohanna Mai A, Al-Khalaf Huda H, Al-Yousef Nujoud, Aboussekhra Abdelilah
King Faisal Specialist Hospital and Research Center, Department of Biological and Medical Research, MBC # 03-66, PO BOX 3354, Riyadh 11211, KSA.
Nucleic Acids Res. 2007;35(1):223-33. doi: 10.1093/nar/gkl1075. Epub 2006 Dec 7.
p16INK4a and p21WAF1, two major cyclin-dependent kinase inhibitors, are the products of two tumor suppressor genes that play important roles in various cellular metabolic pathways. p21WAF1 is up-regulated in response to different DNA damaging agents. While the activation of p21WAF1 is p53-dependent following -rays, the effect of ultraviolet (UV) light on p21WAF1 protein level is still unclear. In the present report, we show that the level of the p21WAF1 protein augments in response to low UVC fluences in different mammalian cells. This up-regulation is mediated through the stabilization of p21WAF1 mRNA in a p16INK4a-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, p16INK4a is also an important regulator of the cellular response to UV damage.
p16INK4a和p21WAF1是两种主要的细胞周期蛋白依赖性激酶抑制剂，它们是两个肿瘤抑制基因的产物，在各种细胞代谢途径中发挥重要作用。p21WAF1在受到不同的DNA损伤剂刺激时会上调。虽然在γ射线照射后p21WAF1的激活是p53依赖性的，但紫外线（UV）对p21WAF1蛋白水平的影响仍不清楚。在本报告中，我们表明，在不同的哺乳动物细胞中，低剂量UVC照射会使p21WAF1蛋白水平升高。在人和小鼠细胞中，这种上调是通过以p16INK4a依赖性方式稳定p21WAF1 mRNA来介导的。此外，使用经p16-siRNA处理的人皮肤成纤维细胞，我们发现p16控制mRNA结合蛋白HuR的紫外线依赖性细胞质积累。此外，HuR免疫沉淀显示，HuR与p21 mRNA的紫外线依赖性结合与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对于紫外线依赖性p53的有效上调是必需的，这也需要HuR。这些结果表明，除了在细胞增殖中的作用外，p16INK4a也是细胞对紫外线损伤反应的重要调节因子。
