MUTANT P53 GAIN OF FUNCTION IN TUMORIGENESIS

突变 P53 在肿瘤发生中的功能获得

• 批准号: 6150175
• 负责人: GERARD PAUL ZAMBETTI
• 金额: $ 24.12万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150175
• 关键词: athymic mouse; carcinogenesis; cell line; gel mobility shift assay; gene expression; gene mutation; genetic mapping; genetic promoter element; genetic transcription; human genetic material tag; multidrug resistance; neoplastic transformation; nucleic acid sequence; p53 gene /protein; polymerase chain reaction; protein structure function; tissue /cell culture; transfection; tumor suppressor genes; tumor suppressor proteins

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer and tumors that express mutant p53 may be associated with a worse prognosis than p53-null cancers. The long-term goal of this research proposal is to further our understanding of the function of mutant p53 in tumorigenesis. Mutant p53 enhances the tumorigenic potential of p53-negative cell lines and this activity correlates with its ability to selectively transactivate the human multi-drug resistance (MDR1) promoter. In our previous funding period, we established that: 1) mutant p53 can regulate expression of the endogenous MDR1 gene as well as the endogenous c-myc gene; 2) mutant p53 transactivation of the c-myc promoter is mediated by sequences located downstream from the transcription start site; 3) the mutant p53 response element in the c-myc gene is not an enhancer and exhibits position and orientation dependent function; and 4) mutant p53 transactivation requires the C-terminal domain, which binds RNA and single-strand (ss) DNA. These results lead to a testable hypothesis that mutant p53 functions in transactivaion through an RNA-dependent mechanism that may be similar to the model proposed for the regulation of the human immunodeficiency virus LTR promoter by the TAT transactivator. To continue our studies on mutant p53 gain of function in tumorigenesis, we propose to address the following specific questions: 1) Does mutant p53 accelerate tumorigenesis in vivo; 2) What is the role of the C- terminus of mutant p53 in gain of function; 3) What is the nature of the mutant p53 response element in the c-myc and MDR1 promoters; and 4) Does mutant p53 function in transactivation and tumorigenicity through an RNA dependent mechanism? Our findings demonstrate significant differences in the structural requirements for wild-type and mutant p53 function, which may provide an exploitable basis for developing therapeutic approaches to treating cancer. The studies proposed here will build on these observations and contribute to our understanding of how mutation of p53 enhances cell growth and tumorigenicity.

p53肿瘤抑制基因是最常见的突变基因 表达突变体p53的人类癌症和肿瘤可能与 比p53-null癌的预后更糟糕。 这个长期目标 研究建议是为了进一步了解 肿瘤发生中的突变p53。 突变体p53增强了p53阴性细胞的致瘤潜力 线条和此活动与其选择性的能力相关 反式激活人类多药抗性（MDR1）启动子。 在我们的 以前的资金期，我们确定：1）突变体P53可以调节 内源性MDR1基因以及内源C-MYC的表达 基因; 2）C-MYC启动子的突变体p53介导 通过转录起始站点下游的序列； 3） C-MYC基因中的突变p53响应元件不是增强子， 表现出位置和方向依赖性功能； 4）突变体P53 反式激活需要C末端结构域，该结构域结合RNA和 单链（SS）DNA。 这些结果导致可检验的假设 该突变体p53通过RNA依赖性在transactivaion中起作用 可能与为调节提出的模型相似的机制 TAT的人类免疫缺陷病毒LTR启动子 反式激活器。 为了继续我们关于突变p53肿瘤发生功能获得的研究， 我们建议解决以下特定问题：1）突变体 p53体内加速肿瘤发生； 2）c-的作用是什么 突变体p53的末端在功能上获得； 3）什么是什么 C-MYC和MDR1启动子中的突变p53响应元件； 4）做 突变体p53通过RNA在反式激活和肿瘤性中的功能 依赖机制？ 我们的发现表明有显着差异 在野生型和突变p53功能的结构要求中， 这可能为开发治疗性提供可利用的基础 治疗癌症的方法。 这里提出的研究将基于 这些观察结果并有助于我们对突变的理解 p53增强了细胞的生长和肿瘤性。