TRANSCRIPTIONAL REPRESSION AND P53 DEPENDENT APOPTOSIS

描述：(逐字改编自调查人员的摘要)P53 肿瘤抑制基因继续保持着最大的区别 人类癌症中频繁突变的基因。强大的选择 癌症中的p53突变被认为是由于它有能力 诱导细胞程序性死亡(细胞凋亡)。来自几个组织的证据 表明P53诱导的细胞凋亡并不依赖于其最好的- 特征性的活性，转录激活。这项提议旨在 为了鉴定一种新的P53活性，序列特异性转录 压抑。野生型(Wt)p53在正常和肿瘤细胞中的诱导 对Map4的转录抑制，它编码了一个无处不在的- 表达了微管聚合蛋白。MAP4在中国的过表达 细胞发生P53依赖的凋亡延迟死亡的出现 细胞，验证这一过程对细胞凋亡的重要性。在稳定的- 转染细胞后，Map4启动子可通过 P53是一个异源基因。该启动子的一个片段可以相互作用 细胞提取液中含有突变型P53蛋白，但无突变型P53蛋白。最新数据 表明除了Map4，P53还抑制其他编码基因 微管的组成部分。对其作用机制的阐明 P53的转录抑制可能是迈向 了解这种蛋白质对肿瘤的抑制作用。了解其他人 P53介导的抑制的靶基因也将是重要的。这 该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.