Transcriptional Regulations of Oncongenic Properties of Mutant P53

描述(申请人提供)：p53肿瘤抑制基因失活的主要机制是错义突变，从而导致产生一种具有促癌能力的突变蛋白。虽然突变型P53可以干扰野生型P53的功能，但大多数表达突变P53的人类癌症都失去了野生型P53。突变型P53蛋白作为癌基因发挥作用至少有两个主要机制：第一个机制涉及其他肿瘤抑制蛋白的物理失活，如其家族成员p63和p73，另一个机制依赖于其调节基因表达的能力。对于突变型p53如何调控在人类癌症中起关键作用的特定基因靶点，提供机械性解释的数据很少。鉴于P53突变的高频率和突变型P53在促进癌症发展中的既定作用，对该癌基因转录调控活性的详细了解可能会为靶向失活其促癌活性开辟新的机会。这一建议的主要假设是，突变的p53与其他转录因子合作，调节与细胞生长、生存和化疗耐药有关的基因。该研究计划将详细分析涉及突变型p53和ets2的转录调控复合体的形成，该转录因子复合体的序列特异性结合活性的特征，以及该复合体对突变型p53‘S的贡献 致癌作用。这三个特异性目的是：特异性目的1：确定Ets2在突变型P53‘S转录调控中的作用。特异性目标2：确定突变型P53和Ets复合体在调节衰老和异常RAS信号中的作用。具体目标3：确定突变型P53转录组中的责任。

DESCRIPTION (provided by applicant): The major mechanism for the inactivation of the p53 tumor suppressor gene is missense mutations, which consequently result in the production of a mutant protein with the ability to promote cancer. Although mutant p53 can interfere with the function of wildtype p53, the majority of human cancers that express mutant p53 have lost wildtype p53. There are at least two major mechanisms through which the mutant p53 protein functions as an oncogene: the first involves the physical inactivation of other tumor suppressor proteins such as its family members, p63 and p73, and the other is dependent on its ability to regulate gene expression. There is a paucity of data that provide a mechanistic explanation of how mutant p53 regulates specific gene targets that play key roles in human cancer. Given the high frequency of p53 mutations and the established role of mutant p53 in promoting cancer development, a detailed understanding of this oncogene's transcriptional regulatory activity may open novel opportunities for targeted inactivation of its carcinogenesis promoting activities. The overarching hypothesis of this proposal is that mutant p53 cooperates with other transcription factors to regulate genes involved in cell growth, survival and chemotherapy resistance. The research plan will provide a detailed analysis of the formation of a transcriptional regulatory complex involving mutant p53 and ETS2, a characterization of the sequence specific binding activity of this transcription factor complex, and the contribution of this complex to mutant p53's oncogenic function. The three specific aims are: Specific Aim 1: Determine the role of ETS2 in mutant p53's regulation of transcription. Specific Aim 2: Determine the role of mutant p53 and ETS complexes in the regulation of senescence and aberrant Ras signaling. Specific Aim 3: Identification of liabilities in the mutant p53 transcriptome.