MUTANT P53 GAIN OF FUNCTION IN TUMORIGENESIS

p53抑癌基因是肿瘤细胞中最常发生突变的基因。 表达突变型p53人类癌症和肿瘤可能与 比p53基因缺失的癌症预后更差。 长期目标是 研究建议是为了进一步了解 突变型p53在肿瘤发生中的作用 突变型p53增强p53阴性细胞的致瘤性 这种活性与其选择性地 反式激活人多药耐药（MDR 1）启动子。 在我们 在前一个基金期间，我们确定：1）突变型p53可以调节 内源性MDR 1基因以及内源性c-myc基因的表达 2）c-myc启动子的突变型p53反式激活被介导 通过位于转录起始位点下游的序列; 3） c-myc基因中的突变型p53应答元件不是增强子， 显示位置和方向依赖性功能;和4）突变型p53 反式激活需要C-末端结构域，其结合RNA， 单链DNA。 这些结果导致了一个可检验的假设 突变型p53通过RNA依赖性的转录激活， 可能类似于为该条例提出的模式的机制 人免疫缺陷病毒LTR启动子的达特 反式激活因子 为了继续研究突变型p53在肿瘤发生中的功能获得， 我们建议解决以下具体问题：1）突变体是否 p53在体内加速肿瘤发生; 2）C- 突变型p53末端在功能获得中的作用; 3）突变型p53末端的性质是什么？ c-myc和MDR 1启动子中的突变型p53应答元件;和4） 突变型p53通过RNA在反式激活和致瘤性中起作用 依赖机制？ 我们的研究结果表明， 在野生型和突变型p53功能的结构要求中， 这可能为开发治疗性药物提供可利用的基础。 治疗癌症的方法。 这里提出的研究将建立在 这些观察有助于我们理解突变 p53的表达增强细胞生长和致瘤性。

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.