Defective p53 synthesis following DNA damage and cancer development

DNA 损伤和癌症发展后 p53 合成缺陷

• 批准号: 7773947
• 负责人: Da-Qing Yang
• 金额: $ 8万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7773947
• 关键词: 5' Untranslated Regions; Apoptosis; Area; Binding; Cancer cell line; Cell Cycle Arrest; Cell Line; Cells; Cellular Stress; Cues; DNA Damage; DNA Sequence; Development; Event; Exhibits; Exposure to; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Human; Internal Ribosome Entry Site; Lead; Link; MDM2 gene; MDM2 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Mutate; Pathogenesis; Play; Post-Translational Protein Processing; Protein p53; Proteins; Regulation; Research; Role; Signal Transduction; TP53 gene; Testing; Trans-Activators; Transcriptional Activation; Translational Regulation; Translations; Tumor Suppressor Proteins; Up-Regulation; anticancer research; cancer cell; carcinogenesis; cell injury; cell transformation; chemical carcinogen; chemotherapeutic agent; cytotoxic; environmental agent; genetic regulatory protein; insight; neoplastic cell; novel; p53-binding protein; public health relevance; research and development; response; tumorigenesis; tumorigenic; ultraviolet; ultraviolet irradiation

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.

描述(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损伤的反应中发挥关键作用。这种抑制和维持是通过DNA损伤后P53蛋白的积累和P53诱导的一系列基因产物的转录激活来实现的，如p21和PUMA，以介导细胞周期停滞或细胞凋亡。由于DNA损伤后P53蛋白水平的升高被认为是导致细胞周期停滞或细胞凋亡的重要因素，因此DNA损伤后P53积聚的机制一直是近二十年来癌症研究的一个主要领域。 虽然人们普遍认为P53的积累是通过与MDM2蛋白的相互作用来调节蛋白质稳定的，但有明确的证据表明，DNA损伤导致P53合成增加也有助于P53的诱导。然而，调控P53翻译以应对DNA损伤的机制仍然知之甚少。我们有一个新的发现，在P53基因的5‘非翻译区(UTR)中存在一个内部核糖体进入位点(IRES)序列。IRES序列允许在细胞或遗传毒性条件下进行帽子无关的蛋白质翻译。我们推测，该IRES序列在调节DNA损伤反应中P53的合成方面发挥关键作用。我们最近的结果也提供了初步证据，DNA损伤后P53合成缺陷可能会导致表达野生型P53的肿瘤细胞恶性转化。该项目的长期目标是进一步研究IRES对P53的翻译调控机制(S)，以响应不同的DNA损伤信号，如化疗药物和紫外线照射，并确定P53 IRES活性的变化是否会导致癌细胞的致瘤转化。这一发现可能有助于更好地理解DNA损伤后P53的合成，并为P53抑癌基因失活与癌症发病机制之间的功能联系提供新的见解。 公共卫生相关性：在这个项目中，我们将分析P53肿瘤抑制因子在环境线索和化疗药物引起的DNA损伤时的翻译调节。此外，我们还将研究DNA损伤后P53合成缺陷与癌细胞致瘤转化的关系。该项目的发现可能有助于更好地理解DNA损伤后P53的合成，并为P53肿瘤抑制基因失活在癌症发病机制中的作用提供新的见解。