The Role of Double Strand Breaks in Carcinogenesis

描述：(申请人提供)P53和细胞凋亡的诱导 体内对电离辐射和其他应激源的反应差异很大 正常组织之间、组织内细胞类型之间以及肿瘤之间 类型。我们的长期目标是了解这种组织的基础 专一性。一种方法是分析P53的组织特异性。 P53上游调控因子基因突变体的反应途径， 特别是P13K家族成员DNAPK和ATM。这些分析表明， 响应伽马辐射(1)DNAPK不需要上调P53或 细胞凋亡。事实上，DNAPK的突变使细胞，甚至是p53缺失的细胞，对 细胞凋亡。这表明了一种新的依赖于DNAPK的抗细胞凋亡途径。 (2)ATM是上调某些组织中P53和细胞凋亡所必需的，但不是 在所有组织中都是必需的，如上皮细胞，表明有代偿性的 调控P53和细胞凋亡的途径及其相对重要性 不同组织类型的代偿途径不同。(3)DNAPK和ATM 在两个基因同时突变中进行功能协作导致 胚胎发育早期的合成致死性。我们建议(1)确定是否 DNAPK突变还可以使P53缺失的肿瘤细胞辐射增敏，并对 鉴定这一新的依赖DNAPK的抗凋亡途径，(2)确定 如果DNAPK、ATM和ATR在体内调控P53和细胞凋亡方面是多余的， (3)确定DNAPK ATM致死性的形态和细胞基础 复合突变胚胎，如果改变了对p53或细胞凋亡的调控 导致了这一缺陷。理解P13的功能相互作用 KS，在调控P53、细胞凋亡、发育和癌变水平上的作用 是应用从细胞中获得的知识的必要环节 把培养模型带到诊所。

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.