Defective p53 synthesis following DNA damage and cancer development

描述（由申请人提供）：暴露于环境因素，如紫外线（UV）照射、化学致癌物和化疗药物，会导致DNA损伤，导致恶性转化和致癌。p53肿瘤抑制因子通过抑制细胞转化和维持细胞的遗传完整性，在细胞对DNA损伤的反应中起关键作用。这种抑制和维持是通过DNA损伤后p53蛋白的积累和p53诱导的一些基因产物（如p21和PUMA）的转录激活来介导细胞周期阻滞或细胞凋亡来实现的。由于p53蛋白水平升高被认为在DNA损伤后启动导致细胞周期阻滞或凋亡的事件中起重要作用，因此DNA损伤后p53积累的机制一直是过去二十年癌症研究的主要领域。

DESCRIPTION (provided by applicant): Exposure to environmental agents, such as ultraviolet (UV) irradiation, chemical carcinogens, and chemotherapeutic agents, causes DNA damage that results in malignant transformation and carcinogenesis. The p53 tumor suppressor plays a critical role in cellular responses to DNA damage by suppressing cell transformation and by maintaining the genetic integrity of the cell. The suppression and maintenance are achieved through accumulation of the p53 protein after DNA damage and through p53-induced transcriptional activation of a number of gene products, such as p21 and PUMA, to mediate either cell cycle arrest or apoptosis. Since elevated levels of the p53 protein are believed to be important in initiating the events leading to cell cycle arrest or apoptosis after DNA damage, the mechanism of p53 accumulation after DNA damage has been a major area of cancer research for the past two decades. Although it is widely accepted that the accumulation of p53 is regulated by protein stabilization through its interaction with MDM2 protein, there is clear evidence indicating that increased synthesis of p53 in response to DNA damage also contributes to the induction of p53. However, the mechanisms underlying the regulation of p53 translation in response to DNA damage are still poorly understood. We have made a novel discovery that an internal ribosome entry site (IRES) sequence is present in the 5'-untranslated region (UTR) of the p53 mRNA. IRES sequences allow cap-independent protein translation under cyto- or genotoxic conditions. We hypothesize that this IRES sequence plays a key role in regulating p53 synthesis in response to DNA damage. Our recent results have also provide initial evidence that defective p53 synthesis after DNA damage may lead to malignant transformation of tumor cells that express wild-type p53. The long term goal of this project is to further study the mechanism(s) underlying the translational regulation of p53 by the IRES in response to various DNA damage signals, such as chemotherapeutic agents and UV irradiation, and to determine whether alteration in p53 IRES activity could result in tumorigenic transformation in cancer cells. The findings from this proposal may lead to a better understanding of p53 synthesis following DNA damage and provide new insight into the functional link between p53 tumor suppressor inactivation and the pathogenesis of cancer. PUBLIC HEALTH RELEVANCE: In this project, we will analyze translational regulation of the p53 tumor suppressor in response to DNA damage caused by environmental cues and chemotherapeutic agents. Moreover, we will also examine the relationship between defective p53 synthesis after DNA damage and the tumorigenic transformation of cancer cells. The findings from this project may lead to a better understanding of p53 synthesis following DNA damage and provide new insight into the mechanisms of p53 tumor suppressor inactivation in the pathogenesis of cancer.