Arsenic Induced Miotic Arrest Associated Apoptosis

砷诱导的缩瞳抑制相关的细胞凋亡

• 批准号: 6687343
• 负责人: J CHRISTOPHER STATES
• 金额: $ 26.87万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687343
• 关键词: Chinese; aneuploidy; antisense nucleic acid; apoptosis; arsenic; basal cell carcinoma; cell growth regulation; chemical carcinogenesis; cyclins; flow cytometry; gene mutation; human genetic material tag; human tissue; p53 gene /protein; phosphorylation; squamous cell carcinoma; ultraviolet radiation

DESCRIPTION (provided by applicant): Arsenic is a natural contaminant of drinking water in many parts of the world, is a known human carcinogen and is #1 on the EPA list of hazardous chemicals. Cancers most often associated with chronic arsenism are squamous and basal cell carcinomas of the skin. How arsenic causes cancer is unknown. However, the National Research Council Report on Arsenic in Drinking Water concluded that the most likely mode of action is induction of numerical and structural chromosomal abnormalities. Arsenite, the carcinogenic form of arsenic found in drinking water, disrupts mitosis causing an anaphase delay and induces aneuploidy in normal diploid human fibroblasts and peripheral blood lymphocytes, and mitotic arrest associated apoptosis (MAAA) in p53 deficient human fibroblasts. The sensitivity of p53 deficient human cells to arsenite induced MAAA suggests that the mechanism of arsenite carcinogenesis is different than sunlight induced skin carcinogenesis in which p53 mutation is an early and common event. The hypothesis to be investigated is that p53 relieves the arsenite-induced anaphase block by activation of the G2 checkpoint response which inactivates cyclin B/cdc2 and derepresses the mitotic exit network and allow the cells to escape arsenite induced MAAA. It is the prevention of apoptosis in arsenic intoxicated cells that allows genetic instability (aneuploidy) after mitotic disruption. Identification of the cellular factors that interact with p53 or the p53 regulated genes to prevent mitotic arrest associated apoptosis and to allow cells to proceed through mitosis with a delay will provide valuable information regarding the mode of action of arsenite. The specific aims proposed are: 1.) Determine activation of the G2 checkpoint pathway in p53(+) and p53(-) cells arrested by arsenite in mitosis; 2.) Test by overexpression and targeted knockdown of G2 checkpoint proteins the role of G2 checkpoint activation in the escape from arsenite induced anaphase block; 3.) Test whether arsenic associated skin tumors are p53 wild type or mutant. The results of these studies will identify players mediating release from arsenite induced mitotic arrest, and will provide valuable information on the mechanism of arsenic induced carcinogenesis, clues to the usefulness of arsenite as a chemotherapeutic agent and valuable information on the mode of action of mitosis disrupting drugs in killing human cells.

描述（由申请人提供）：砷在世界许多地方是饮用水的天然污染物，是已知的人类致癌物，在EPA危险化学物质清单上排名第一。最常与慢性砷有关的癌症是皮肤的鳞状和基底细胞癌。砷如何引起癌症。但是，国家研究委员会关于饮用水中砷的报告得出结论，最有可能的作用方式是诱导数值和结构性染色体异常。砷是在饮用水中发现的砷的致癌形式，破坏有丝分裂，导致后期延迟，并诱导正常二倍体人类成纤维细胞和周围血液淋巴细胞的非整倍性，以及有丝分裂的血液淋巴结症，以及有丝分裂的相关性凋亡（MAAA）在p53 p53 defbibro fibro fibro tefibro fibro tefibro tefibro fibro bibro bibrosprosts中。 p53缺乏人类细胞对砷诱导的MAAA的敏感性表明，砷矿石发生的机理与阳光引起的皮肤致癌作用不同，其中p53突变是早期且常见的事件。要研究的假设是，p53通过激活G2检查点响应来缓解砷矿诱导的后期阻滞，该响应使细胞周期蛋白B/CDC2失活并改性脱离有丝分裂的出口网络并允许细胞逃脱砷矿诱导的MAAA。这是预防砷陶醉细胞中凋亡的原因，在有丝分裂破坏后允许遗传不稳定性（非整倍性）。鉴定与p53或p53调控基因相互作用的细胞因子，以防止有丝分裂停滞相关的凋亡，并允许细胞通过有丝分裂进行延迟进行有丝分裂，这将提供有关砷矿作用方式的宝贵信息。提出的具体目的是：1。）确定p53（+）和p53（ - ）细胞在有丝分裂中捕获的G2检查点途径的激活； 2.）通过过表达和靶向敲低G2检查点蛋白的测试G2检查点在逃离阿森特诱导的后期块中的作用； 3.）测试砷相关的皮肤肿瘤是p53野生型还是突变体。这些研究的结果将确定介导砷诱导有丝分裂停滞释放的参与者，并将提供有关砷诱导的癌变机制的有价值信息，这是砷作为化学治疗剂的有用性以及有关破坏人类细胞有效性药物的作用方式的有价值信息的线索。