Regulation Of Mutant P53

突变体P53的调控

• 批准号: 6668436
• 负责人: Dan L. Longo
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6668436
• 关键词: B cell lymphoma; biological signal transduction; cell growth regulation; cell line; gene induction /repression; mutant; neoplasm /cancer genetics; oncoproteins; p53 gene /protein; phorbols; transforming growth factors

One of the most effected genes in the human tumors is p53. About 60% of human cancers contain mutation in p53 gene. Although the regulation of p53 is well studied, very little is known about the regulation of mutant p53. We have shown previously that a human B-lymphoma cell line (RL) harboring mutant p53, which is refractory to the growth inhibitory effects of transforming growth factor-beta (TGF-beta),can be rendered sensitive to TGF-beta by induction of receptors for TGF-beta with low concentrations of phorbol myristate acetate (PMA). We have also shown the growth inhibitory effect of TGF-beta was associated with a down regulation of mutant p53. Our goal is to understand the mechanisms involved in the down regulation of mutant p53 by TGF-beta, and to examine whether the down regulation of mutant p53 is responsible for the TGF-beta-mediated growth suppression. We are also interested in identifying the gain-of-functions properties of mutant p53 in RL cells. The mutant p53 from RL and wild type p53 will be transfected separately in a human colon tumor cell line, HCT 116, which has p53 null background. The RNA from these cells will be used in micro array analysis using home made cDNA array chip to examine the expression pattern of several thousand genes. Genes will be identified that are differentially regulated by different p53.

p53 是人类肿瘤中受影响最大的基因之一。大约60%的人类癌症含有p53基因突变。尽管p53的调控已得到充分研究，但对突变体p53的调控却知之甚少。我们之前已经证明，携带突变体p53的人B淋巴瘤细胞系（RL）对转化生长因子-β（TGF-β）的生长抑制作用具有抵抗力，可以通过诱导具有低浓度佛波醇肉豆蔻酸酯乙酸酯 (PMA) 的 TGF-β 受体。我们还表明 TGF-β 的生长抑制作用与突变体 p53 的下调有关。我们的目标是了解 TGF-β 下调突变型 p53 的机制，并检查突变型 p53 的下调是否与 TGF-β 介导的生长抑制有关。我们还对确定 RL 细胞中突变体 p53 的功能获得特性感兴趣。来自 RL 的突变型 p53 和野生型 p53 将分别转染到人类结肠肿瘤细胞系 HCT 116 中，该细胞系具有 p53 无效背景。来自这些细胞的RNA将用于微阵列分析，使用自制的cDNA阵列芯片来检查数千个基因的表达模式。将鉴定受不同 p53 差异调节的基因。