Defective p53 synthesis following DNA damage and cancer development

描述（由申请人提供）：暴露于环境因子，如紫外线（UV）照射、化学致癌物和化疗剂，会导致DNA损伤，从而导致恶性转化和致癌作用。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。抑制和维持是通过DNA损伤后p53蛋白的积累和通过p53诱导的许多基因产物（如p21和p53 A）的转录激活来介导细胞周期停滞或凋亡。由于p53蛋白水平的升高被认为在启动导致DNA损伤后细胞周期停滞或凋亡的事件中是重要的，因此DNA损伤后p53积累的机制在过去二十年中一直是癌症研究的主要领域。 尽管人们普遍认为p53的积累是通过其与MDM 2蛋白的相互作用而受到蛋白质稳定化的调节，但有明确的证据表明，响应于DNA损伤的p53合成增加也有助于p53的诱导。然而，对DNA损伤后p53翻译的调控机制仍知之甚少。我们发现p53 mRNA的5 '非翻译区（UTR）存在一个内部核糖体进入位点（IRES）序列。IRES序列允许在细胞毒性或遗传毒性条件下的帽非依赖性蛋白质翻译。我们推测，这个IRES序列在调节p53合成响应DNA损伤中起着关键作用。我们最近的研究结果也提供了初步的证据表明，DNA损伤后有缺陷的p53合成可能会导致表达野生型p53的肿瘤细胞的恶性转化。本项目的长期目标是进一步研究IRES对p53的翻译调节机制，以响应各种DNA损伤信号，如化疗药物和紫外线照射，并确定p53 IRES活性的改变是否会导致癌细胞的致瘤性转化。这项研究结果可能会导致更好地理解DNA损伤后p53的合成，并提供新的见解p53肿瘤抑制基因失活和癌症发病机制之间的功能联系。 公共卫生相关性：在这个项目中，我们将分析p53肿瘤抑制基因的翻译调控对环境因素和化疗药物引起的DNA损伤的反应。此外，我们还将研究DNA损伤后p53合成缺陷与癌细胞致瘤性转化之间的关系。该项目的发现可能会导致更好地理解DNA损伤后p53的合成，并为癌症发病机制中p53肿瘤抑制因子失活的机制提供新的见解。

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.