ACETYLTRANSFERASES AND ONCOGENESIS

描述：(逐字改编自调查人员的摘要)这个项目 旨在加深对未知分子事件的理解 肿瘤发生，特别是翻译后乙酰化所起的作用 肿瘤抑制因子P53蛋白。扰乱增长停滞反应和 已知p53基因错义突变所致的细胞凋亡途径 对肿瘤克隆的选择性优势，并使其难以 几种抗肿瘤治疗。这种无动于衷，至少是 部分原因是大多数p53突变体不能 结合到P53特异的DNA结合部位，从而激活 生长调节基因。通过引入正常的p53基因进行直接基因治疗 已经尝试过将基因导入肿瘤细胞，但结果不确定。 可能是由于几个p53突变体固有的显性负活性(S)所致 蛋白质。因此，从P53中挽救正常活动(S)的可能性 P53突变本身似乎是一种有吸引力的替代方法。研究表明 P53突变体的DNA结合能力可以通过以下方法在体外重建 添加抗P53单抗支持这一观点，并提供了 有价值的证据表明P53的结构是灵活的。我现在有了 证明P53的翻译后乙酰化是由 乙酰基转移酶P/CaF恢复突变型p53序列特异性DNA结合 蛋白质在其他方面不能与DNA结合。此外， P/CAF在P53基因突变转化细胞系中的过表达 基因挽救了转化细胞的大多数表型，包括正常的 形态类型和对遗传毒性物质的反应性，如紫外线照射。 这些发现表明P/CAF是细胞内的重要成分 通常可防止肿瘤发生的通路级联反应。它们还揭示了 存在一种新的使P53乙酰化的分子机制，以及 也许在其他调节蛋白中，MICHT决定了肿瘤的敏感性。 从细胞到治疗剂。我在这里提出了遗传和生化方法 观察P/CAF对肿瘤的抑制作用。

DESCRIPTION: (adapted verbatim from the investigator's abstract) This project aims to develop an understanding of yet unknown molecular events involved in oncogenesis, specifically the role played by post-translational acetylation of the tumor suppressor p53 protein. Disruption of growth-arrest responses and apoptotic pathways by missense mutations of the p53 gene is known to confer a selective advantage to neoplastic clones and to render them refractory to several anti-neoplastic treatments. Such unresponsiveness is, at least partially, sustained by the fact that most of p53 mutants are incapable of binding to p53-specific DNA-binding sites and thus, of activating growth-regulatory genes. Direct gene therapy, by introduction of a normal p53 gene into tumor cells has been attempted but yielded inconclusive results, probably due to dominant negative activity(s) intrinsic to several p53 mutant proteins. Thus, the possibility of rescuing normal activity(s) from a p53 from a p53 mutant per se appears to attractive alternative approach. Studies showing that the DNA binding ability of p53 mutants can be reestablished in vitro by the addition of anti-p53 monoclonal antibodies, support this view and provide valuable evidence that the structure of p53 is flexible. I have now demonstrated that post-translational acetylation of p53 by the acetyl-transferase, P/CAF, restores sequence specific DNA-binding of p53 mutant proteins otherwise dysfunctional for binding to DNA. Furthermore, overexpression of P/CAF in transformed cell lines carrying mutations of the p53 gene rescues most phenotypes of transformed cells, including a normal morphotype and responsiveness to genotoxic agents, such as UV-irradiation. These findings implicate P/CAF as a crucial component of an intracellular pathway cascade which normally prevents oncogenesis. They also reveal the existence of a novel molecular mechanism whereby acetylation of p53, and perhaps of other regulatory proteins, micht determine the sensitivity of tumor cells to therapeutic agents. I propose here genetic and biochemical approaches to examine how P/CAF exerts its tumor-suppressive activity.