MOLECULAR BIOLOGY OF CELLULAR INJURY

该研究小组的主要重点是研究对下列问题的反应： 哺乳动物细胞中的遗传毒性应激。这包括克隆和 多种DNA损伤诱导（DDI）基因的表征， p53在调控中的作用研究表明， 基因，p21 CIP 1/WAF 1，BCL 2，BCL-X，BAX，MCL 1，β-聚合酶，O 6- 甲基鸟嘌呤DNA甲基转移酶、c-jun、c-fos、拓扑异构酶I和 II、金属硫蛋白和泛素。了解DNA损伤的作用 确定细胞对细胞毒性剂的敏感性的反应， 例如用于癌症治疗是主要目的。一个重要 所有细胞对遗传毒性应激的反应是细胞周期的延迟 这是由DNA损伤引起的。这些延迟是调解的 可能包括gadd基因，这两个基因都是DDI 和生长停滞诱导型。该项目的主要部分集中在 1）研究gadd基因的表达， 这五个基因的cDNA和基因组克隆的表征; 2)抑癌基因p53在介导DNA损伤中的作用 3）这些基因的调控，特别强调 gadd 45; 4）gadd蛋白的表征和相互作用 蛋白质; 5）阐明这些基因的功能; 6） gadd及其相关基因在细胞凋亡中的作用; 7）转基因小鼠的应用 研究这些基因在体内的作用的模型; 8） 这些基因在已知对各种肿瘤敏感的人肿瘤细胞系中， 化疗药物。特别令人感兴趣的是我们最近的发现， GADD 45基因受p53调控，Gadd 45蛋白与 这两种蛋白质都参与细胞周期调节和DNA修复。的 p53对GADD 45及其相关蛋白的调控具有重要意义。 在癌症治疗中的影响，考虑到大约三分之二的人， 的人肿瘤缺乏正常的p53功能。

The major focus of this research group is the study of responses to genotoxic stress in mammalian cells. This has included the cloning and characterization of a variety of DNA-damage-inducible (DDI) genes and the role of p53 in their regulation. Studies have involved the gadd genes, p21CIP1/WAF1, BCL2, BCL-X, BAX, MCL1, beta-polymerase, O6- methylguanine DNA methyltransferase, c-jun, c-fos, topoisomerases I and II, metallothionein, and ubiquitin. Understanding the role of DNA-damage responses in determining the cellular sensitivity to cytotoxic agents, such as used in cancer therapy, is a major objective. An important response to genotoxic stress in all cells are delays in cell cycle progression which are induced by DNA damage. These delays are mediated by various genes and probably include the gadd genes which are both DDI and growth-arrest inducible. The major portions of this project focus on: 1) the study of the expression of the gadd genes and characterization of the cDNA and genomic clones for these five genes; 2) the role of the tumor suppressor p53 in mediating DNA damage responses; 3)the regulation of these genes with particular emphasis on gadd45; 4) the characterization of the gadd proteins and interacting proteins; 5) elucidation the function of these genes; 6) the role of the gadd and related genes in apoptosis; 7)the use of transgenic mouse models to study the roles of these genes in vivo; 8) the expression of these genes in human tumor cell lines with known sensitivity to various chemotherapy agents. Of particular interest is our recent findings that the GADD45 gene is p53-regulated and the Gadd45 protein interacts with both proteins involved in both cell-cycle regulation and DNA repair. The regulation of GADD45 and related proteins by p53 has have important implications in cancer therapy considering that approximately two thirds of human tumors lack normal p53 function.