TRANSCRIPTIONAL REPRESSION AND P53 DEPENDENT APOPTOSIS

描述：（逐字改编自研究者摘要）第53页 肿瘤抑制基因仍然保持着最大的区别， 在人类癌症中经常发生突变的基因。强大的选择， 癌症中p53的突变被认为是由于其能够 诱导程序性细胞死亡（凋亡）。来自多个群体的证据 表明p53的凋亡诱导并不依赖于其最好的- 特征活性，转录激活。该提案寻求 为了表征p53的新活性，序列特异性转录因子 镇压在正常和肿瘤细胞中野生型（wt）p53诱导导致 与Map 4的转录抑制有关，Map 4编码一种普遍存在的- 表达微管聚合蛋白。Map 4基因的过表达 经历p53依赖性凋亡的细胞延迟了死亡的出现 细胞，验证了这一过程对凋亡的重要性。稳定地- 在转染的细胞中，Map 4启动子可以通过以下方式赋予负调控： p53的异源基因。该启动子的一个片段可以与 在细胞提取物中含有野生型而非突变型p53蛋白。最近的数据 这表明除了Map 4，p53还抑制其他基因， 微管的组成部分。阐明了 通过p53的转录抑制可能是一个关键步骤， 了解这种蛋白质对肿瘤的抑制作用。理解其他 p53介导的抑制的靶基因也很重要。这 提案旨在实现这些目标。

DESCRIPTION: (adapted verbatim from the investigator's abstract) The p53 tumor suppressor gene continues to hold distinction as the most frequently mutated gene in human cancer. The powerful selection for mutation of p53 in cancer is believed to result from its ability to induce programmed cell death (apoptosis). Evidence from several groups indicates that apoptosis induction by p53 does not rely on its best- characterized activity, transcriptional activation. This proposal seeks to characterize a new activity of p53, sequence-specific transcriptional repression. Wild type (wt) p53 induction in normal and tumor cells leads to transcriptional repression of Map4, which encodes a ubiquitously- expressed microtubule-polymerizing protein. Overexpression of Map4 in cells undergoing p53-dependent apoptosis delays the appearance of dying cells, verifying the importance of this process to apoptosis. In stably- transfected cells, the Map4 promoter can confer negative regulation by p53 to a heterologous gene. A fragment of this promoter can interact with wt but not mutant p53 protein in cell extracts. Recent data indicate that in addition to Map4, p53 represses other genes encoding components of microtubules. Elucidation of the mechanism of transcriptional repression by p53 is likely to be a critical step toward understanding tumor suppression by this protein. Understanding other targets genes of p53-mediated repression will also be important. This proposal seeks to achieve these goals.