The Role of Double Strand Breaks in Carcinogenesis

描述：（申请人提供）在细胞中诱导p53和细胞凋亡。 体内对电离辐射和其他应激源的反应差异很大 在正常组织之间、在组织内的细胞类型之间以及在肿瘤之间， 类型我们的长期目标是了解这种组织的基础 的特异性一种方法是分析p53的组织特异性， p53的假定上游调节子的遗传突变体中的反应途径， 特别是P13K家族成员DNAPK和Atm。这些分析表明， 在对γ辐射的反应中，（1）DNAPK不需要上调p53或 凋亡事实上，DNAPK的突变使细胞，甚至是p53缺失细胞， 凋亡这证明了一种新的DNAPK依赖性抗凋亡途径。 (2)在某些组织中，Atm是上调p53和细胞凋亡所必需的，但不是 所有组织如上皮都需要，表明存在代偿性 调节p53和凋亡的途径以及这些途径的相对重要性 代偿途径因组织类型而异。(3)DNAPK和ATM 在两个基因中同时突变在功能上协作， 胚胎发育早期的合成致死。我们建议（1）确定是否 DNAPK的突变也可以使p53缺失的肿瘤细胞放射增敏， 表征这种新的DNAPK依赖性抗凋亡途径，（2）确定 如果DNAPK、Atm和Atr在体内调节p53和凋亡中是多余的， (3)确定DNAPK Atm致死性的形态学和细胞学基础 复合突变胚胎，如果改变了p53或细胞凋亡的调节， 导致了这种缺陷。了解P13的功能相互作用 Ks在调节p53、凋亡、发生和癌变水平上的作用 对整个动物的研究是应用细胞知识的必要环节 文化模式到诊所

DESCRIPTION: (PROVIDED BY APPLICANT) The induction of p53 and apoptosis in response to ionizing radiation and other stressors in vivo varies greatly between normal tissues, between cell types within a tissue, and between tumor types. Our long-term goal is to understand the basis of this tissue specificity. One approach is to analyze the tissue specificity of the p53 response pathway in genetic mutants of putative upstream regulators of p53, notably the P13K family members DNAPK and Atm. These analyses have shown that in response to gamma radiation (1) DNAPK is not required to upregulate p53 or apoptosis. In fact, mutation in DNAPK sensitizes cells, even p53 null cells, to apoptosis. This demonstrates a novel DNAPK dependent anti-apoptotic pathway. (2) Atm is required to upregulate p53 and apoptosis in some tissue, but is not required in all tissues such as epithelium indicating there are compensatory pathways to regulate p53 and apoptosis and the relative importance of these compensatory pathways varies between tissue types. (3) DNAPK and Atm functionally collaborate in that simultaneous mutation in both genes results in synthetic lethality early in embryogenesis. We propose to (1) determine if mutation in DNAPK can also radiosensitize p53 null tumor cells and to characterize this novel DNAPK dependent anti-apoptotic pathway, (2) determine if DNAPK, Atm and Atr are redundant in regulating p53 and apoptosis in vivo, (3) determine the morphologic and cellular basis of lethality of DNAPK Atm compound mutant embryos, and if altered regulation of p53 or apoptosis contributes to this defect. Understanding the functional interaction of the P13 Ks, in regulating p53, apoptosis, development and carcinogenesis at the level of the whole animal is a necessary link to apply knowledge gained from cell culture models to the clinic.