PIK RELATED KINASES IN THE RESPONSE TO DNA DAMAGE BY UV

太阳紫外线(UV)辐射对DNA的损伤是皮肤的主要原因 癌症，美国最常见的癌症类型。一种细胞“紫外线” 涉及P53肿瘤抑制蛋白激活的反应 进化来保护基因组免受这种太阳威胁。一个完好无损的 复制，防止突变的永久并入。 大约90%的鳞状细胞癌缺乏这种紫外线反应，表明 致癌。 尽管这种保护途径很重要，但目前还不清楚它是如何 紫外线对DNA的损伤导致P53的诱导。一种叫做ATR的基因已经被 在Schreiber组中克隆，似乎是 基于初步数据的UV-P53反应。ATR属于一种新的 所描述的称为PIK相关蛋白的蛋白家族(磷脂酰基 肌醇激酶相关酶)，其中包括突变在 隐性致死性疾病，共济失调毛细血管扩张症。PIK相关的蛋白水解酶 调节细胞应激后的细胞周期停滞，如DNA损伤。 分子和生化方法将被用来检验这一假说 紫外光反应需要ATR或另一个与PIK相关的激酶。 内源性ATR功能将受到抑制，显性负ATR 在可诱导或逆转录病毒系统中表达的等位基因。ATR的作用 然后在UV-DNA反应的个别方面进行检查 损坏。以后的研究将集中在该途径中的其他蛋白质上。 该项目旨在深入了解紫外线的分子机制。 致癌，并可提出预防和预防癌症的方法 治疗皮肤癌和更一般的癌症。

DNA damage by solar ultraviolet (UV) radiation is the major cause of skin cancer, the most common type of cancer in the US. A cellular "UV response" involving activation of the p53 tumor suppressor protein has evolved to protect the genome against this solar threat. An intact response leads to cell cycle arrest and allows DNA to be repaired prior to replication, preventing the permanent incorporation of mutations. Roughly 90% of squamous cell carcinomas lack this UV response indicating the essential function of this pathway in protecting the genome from UV carcinogenesis. Despite the importance of this protective pathway, it is not known how DNA damage by UV leads to p53 induction. A gene called ATR has been cloned in the Schreiber group and appears likely to be the mediator of the UV-p53 response based on preliminary data. ATR belongs to a newly described family of proteins called the PIK-related kinases (phosphatidyl inositol kinase-related kinases), which includes the gene mutated in the recessive lethal disease, ataxia telangiectasia. The PIK-related kinases mediate cell cycle arrest after cellular stresses such as DNA damage. Molecular and biochemical approaches will be used to test the hypothesis that ATR or another PIK-related kinase is required for the UV response. Endogenous ATR function will be inhibited with a dominant negative ATR allele expressed in an inducible or retroviral system. The role of ATR will then be examined in individual aspects of the response to UV-DNA damage. Later studies will focus on other proteins in this pathway including putative substrates for the UV-responsive protein. This project aims to provide insight into the molecular mechanism of UV carcinogenesis and may suggest approaches for the prevention and treatment of skin cancer and cancer more generally.