Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Cold Spring Harb Perspect Biol. 2010 Aug;2(8):a000935. doi: 10.1101/cshperspect.a000935. Epub 2010 Apr 28.
Inactivation of p53 is critical for the formation of most tumors. Illumination of the key function(s) of p53 protein in protecting cells from becoming cancerous is therefore a worthy goal. Arguably p53's most important function is to act as a transcription factor that directly regulates perhaps several hundred of the cell's RNA polymerase II (RNAP II)-transcribed genes, and indirectly regulates thousands of others. Indeed p53 is the most well studied mammalian transcription factor. The p53 tetramer binds to its response element where it can recruit diverse transcriptional coregulators such as histone modifying enzymes, chromatin remodeling factors, subunits of the mediator complex, and components of general transcription machinery and preinitiation complex (PIC) to modulate RNAPII activity at target loci (Laptenko and Prives 2006). The p53 transcriptional program is regulated in a stimulus-specific fashion (Murray-Zmijewski et al. 2008; Vousden and Prives 2009), whereby distinct subsets of p53 target genes are induced in response to different p53-activating agents, likely allowing cells to tailor their response to different types of stress. How p53 is able to discriminate between these different loci is the subject of intense research. Here, we describe key aspects of the fundamentals of p53-mediated transcriptional regulation and target gene promoter selectivity.
p53 的失活对于大多数肿瘤的形成至关重要。因此，阐明 p53 蛋白保护细胞免受癌变的关键功能是一个有价值的目标。可以说，p53 的最重要功能是作为转录因子，直接调节细胞 RNA 聚合酶 II（RNAP II）转录的数百个基因，间接调节数千个其他基因。事实上，p53 是研究最深入的哺乳动物转录因子。p53 四聚体结合到其反应元件上，在那里它可以招募各种转录共激活因子，如组蛋白修饰酶、染色质重塑因子、中介复合物的亚基，以及一般转录机制和起始前复合物（PIC）的组成部分，以调节靶基因座上的 RNAPII 活性（Laptenko 和 Prives 2006）。p53 的转录程序以刺激特异性的方式进行调节（Murray-Zmijewski 等人，2008 年；Vousden 和 Prives 2009 年），其中不同的 p53 靶基因子集在响应不同的 p53 激活剂时被诱导，这可能使细胞能够根据不同类型的应激来调整其反应。p53 如何能够区分这些不同的基因座是一个激烈研究的主题。在这里，我们描述了 p53 介导的转录调节和靶基因启动子选择性的基本原理的关键方面。
