The tumor suppressor p53 regulates c-Maf and Prox-1 to control lens differentiation.
The tumor suppressor p53 regulates c-Maf and Prox-1 to control lens differentiation.
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DOI：
10.2174/156652412802480835
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发表时间：
2012-08
影响因子：
2.5
通讯作者：
F-Y Liu;X-C Tang;M. Deng;P. Chen;W. Ji;X. Zhang;L. Gong;Z. Woodward;J. Liu;L. Zhang;S. Sun;J.-P. Liu;K. Wu;M.-X. Wu;X.-L. Liu;M. Yu;Y. Liu;D. W. Li
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文献类型：
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作者：
F-Y Liu;X-C Tang;M. Deng;P. Chen;W. Ji;X. Zhang;L. Gong;Z. Woodward;J. Liu;L. Zhang;S. Sun;J.-P. Liu;K. Wu;M.-X. Wu;X.-L. Liu;M. Yu;Y. Liu;D. W. Li
抑癌基因p53在调节细胞凋亡和细胞周期进程中起关键作用。此外，p53涉及肌肉、循环系统、眼透镜和各种癌组织中细胞分化的控制。然而，p53控制细胞分化的机制尚未完全了解。在这里，我们提出的证据表明，p53直接调节c-Maf和Prox 1，两个重要的转录因子控制分化的眼透镜。首先，人和鼠c-Maf和Prox 1基因启动子含有真实的p53 DNA结合位点。第二，p53直接结合到在启动子区域中发现的p53结合位点。第三，外源性p53诱导由c-Maf和Prox 1启动子驱动的荧光素酶报告基因的剂量依赖性表达，并且在ChIP测定中p53与两种启动子结合。第四，在体外分化模型中，p53的敲低显著抑制透镜分化，这与c-Maf和Prox 1的表达下调有关。最后，在p53基因敲除小鼠中，c-Maf和Prox 1的表达显著改变。总之，我们的研究结果表明，p53调节透镜分化通过两个重要的转录因子，c-Maf和Prox 1的调制，并通过它们p53从而控制各种分化相关的下游晶体蛋白基因的表达。
The tumor suppressor p53 plays a key role in regulating apoptosis and cell cycle progression. In addition, p53 is implicated in control of cell differentiation in muscle, the circulatory system, ocular lens and various carcinoma tissues. However, the mechanisms by which p53 controls cell differentiation are not fully understood. Here we present evidence that p53 directly regulates c-Maf and Prox1, two important transcription factors controlling differentiation in the ocular lens. First, human and murine c-Maf and Prox1 gene promoters contain authentic p53 DNA binding sites. Second, p53 directly binds to the p53 binding sites found in the promoter regions. Third, exogenous p53 induces dose-dependent expression of the luciferase report gene driven by both c-Maf and Prox1 promoters, and p53 binds to both promoters in the ChIP assays. Fourth, in the in vitro differentiation model, knockdown of p53 significantly inhibits lens differentiation which is associated with downregulated expression of c-Maf and Prox1. Finally, in p53 knockout mice, the expression of c-Maf and Prox1 are significantly altered. Together, our results reveal that p53 regulates lens differentiation through modulation of two important transcription factors, c-Maf and Prox1, and through them p53 thus controls expression of various differentiation-related downstream crystallin genes.