p53 Deficiency Leads to Compensatory Up-Regulation of p16INK4a
p53 Deficiency Leads to Compensatory Up-Regulation of p16INK4a
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DOI：
10.1158/1541-7786.mcr-08-0373
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发表时间：
2009-03-01
影响因子：
5.2
通讯作者：
Li, Baojie
中科院分区：
文献类型：
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作者：
Leong, Wai Fook;Chau, Jenny Fung Ling;Li, Baojie
p53-p21-细胞周期蛋白依赖性激酶和p16（INK 4a）-细胞周期蛋白依赖性激酶途径在预防肿瘤发生中具有平行的功能。在癌症患者中，肿瘤抑制基因p53经常通过突变失活，而p16（INK 4a）通过启动子甲基化沉默。然而，这两种途径之间的相互作用还不太清楚。在这里，我们报告说，p53控制p16（INK 4a）的表达以独特的方式。p53缺陷导致p16（INK 4a）在原代小鼠胚胎成纤维细胞、成骨细胞和各种小鼠器官中的上调，以及p16（INK 4a）启动子活性的增加，而不影响p16（INK 4a）的半衰期。p53的重建，而不是突变p53，恢复了p16（INK 4a）的正确表达。这些结果表明p53在抑制p16（INK 4a）表达中是必需的。然而，响应于遗传毒性应激或nutlin-3处理的p53上调并没有下调p16（INK 4a）。p53也不抑制p16（INK 4a）启动子活性。这些发现表明，p53在抑制p16（INK 4a）表达中具有必要但不充分的作用。p53（-/-）细胞中p16（INK 4a）的升高至少部分地由Ets 1介导，Ets 1是p16（INK 4a）的已知正调节因子，因为p53缺陷通过蛋白质稳定化上调Ets 1，并且Ets 1的敲低下调p53（-/-）小鼠胚胎成纤维细胞中p16（INK 4a）的表达。这些研究揭示了p53丢失的补偿机制，并为在癌症治疗中靶向p53和p16（INK 4a）提供了基础。(Mol Cancer Res 2009;7（3）：354-60）
p53-p21-cyclin-dependent kinase and p16(INK4a)-cyclin-dependent kinase pathways have parallel functions in preventing tumorigenesis. In cancer patients, tumor suppressor p53 is frequently inactivated through mutations, whereas p16(INK4a) is silenced through promoter methylation. However, the interaction between these two pathways is less well understood. Here, we report that p53 controls p16(INK4a) expression in a unique way. p53 deficiency led to up-regulation of p16(INK4a) in primary mouse embryonic fibroblasts, osteoblasts, and various mouse organs, and an increase in the p16(INK4a) promoter activity, without affecting the half-life of p16(INK4a). Reconstitution of p53, but not mutant p53, restored the proper expression of p16(INK4a). These results indicate that p53 is necessary in repressing p16(INK4a) expression. However, up-regulation of p53 in response to genotoxic stress or nutlin-3 treatment did not down-regulate p16(INK4a). p53 did not repress the p16(INK4a) promoter activity either. These findings suggest that p53 has a necessary but not sufficient role in repressing p16(INK4a) expression. p16(INK4a) elevation in p53(-/-) cells is, at least partially, mediated by Ets1, a known positive regulator of p16(INK4a), as p53 deficiency up-regulated Etsl through protein stabilization and knockdown of Ets1 down-regulated p16(INK4a) expression in p53(-/-) mouse embryonic fibroblasts. These studies uncover a compensatory mechanism for the loss of p53 and provide a basis for targeting both p53 and p16(INK4a) in cancer therapy. (Mol Cancer Res 2009;7(3):354-60)