PIK RELATED KINASES IN THE RESPONSE TO DNA DAMAGE BY UV

太阳紫外线（UV）辐射造成的DNA损伤是皮肤病的主要原因。 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“应答”已经 保护基因组免受太阳的威胁完整 反应导致细胞周期停滞，并允许DNA被修复之前， 复制，防止永久性的突变。 大约90%的鳞状细胞癌缺乏这种紫外线反应， 该途径在保护基因组免受紫外线侵害方面的基本功能 致癌作用 尽管这一保护途径很重要，但尚不清楚其作用机制。 紫外线引起的DNA损伤导致p53诱导。一种叫做ATR的基因 克隆在Schreiber组，似乎可能是调解人， UV-p53反应基于初步数据。ATR属于一个新的 描述了一种称为PIK相关激酶（磷脂酰）的蛋白质家族 肌醇激酶相关激酶），其包括在 隐性致死性疾病共济失调毛细血管扩张症PIK相关激酶 在细胞应激如DNA损伤后介导细胞周期停滞。 分子和生物化学的方法将被用来测试的假设 ATR或另一种PIK相关激酶是UV反应所必需的。 内源性ATR功能将被显性负性ATR抑制 在诱导型或逆转录病毒系统中表达的等位基因。ATR的作用 然后将在对UV-DNA的响应的各个方面进行检查 损害以后的研究将集中在这一途径中的其他蛋白质上 包括UV响应蛋白的推定底物。 本项目旨在提供深入了解紫外线的分子机制 致癌作用，并可能提出预防和 治疗皮肤癌和更普遍的癌症。

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.