Role of p53 homologs in DNA repair in human keratinocytes

p53 同源物在人类角质形成细胞 DNA 修复中的作用

• 批准号: 7797798
• 负责人: DENNIS H OH
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797798
• 关键词: Address; Affect; Award; Behavior; Burn injury; Cancer Etiology; Cell Line; Cells; Clinical; DNA Damage; DNA Repair; DNA lesion; DNA photoproducts; Development; Event; Family; Family member; Future; General Population; Genomics; Goals; Health; Healthcare; Heavy Metals; Homologous Gene; Human; In Vitro; Injury; Laboratories; Lead; Life; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Medical; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Mutagenesis; Nucleotide Excision Repair; Oncogenes; Operative Surgical Procedures; Physiology; Population; Process; Protein Isoforms; Protein p53; Proteins; Publishing; Pyrimidine Dimers; Quality of life; Regulation; Resources; Risk; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Source; Squamous cell carcinoma; System; Testing; The Sun; Tissues; Trauma; Travel; Ultraviolet Rays; Undifferentiated; United States; Veterans; Work; Wound Healing; abstracting; base; body system; carcinogenesis; cell type; cost; keratinocyte; keratinocyte differentiation; killings; prevent; repaired; response; restoration; skin disorder; tumor; tumor progression; ultraviolet

DESCRIPTION (provided by applicant): Project Summary/Abstract Non-melanoma skin cancers are the most common malignancies in the general population of the United States and are highly prevalent in the veteran population. While not usually fatal, these skin cancers can be a major source of morbidity, impair quality of life, and utilize significant health care resources. Cumulative DNA damage in epidermal keratinocytes, particularly from solar ultraviolet radiation, is an important factor in the development of non-melanoma skin cancers. In addition, certain therapies for other skin diseases utilize DNA damaging agents that increase the risk of skin cancer. Bulky, distorting DNA lesions are removed by the process of nucleotide excision repair, but little is known about the regulation of DNA repair in keratinocytes. Clinical observations and recent in vitro studies, including those from the PI's laboratory, indicate that human keratinocytes possess unique mechanisms for regulating nucleotide excision repair. Loss of the tumor suppressor, p53, in non-keratinocyte cell types typically results in a loss of repair of the most abundant UVR- induced photoproduct. However, work during the current award period has documented that keratinocytes require loss of both p53 and another member of the family-p63-before repair is compromised. Furthermore, recent work in the PI's laboratory suggests that a dual deficiency in p53 and p63 is associated with impaired nucleotide excision repair in squamous cell carcinomas that could be exploited to preferentially kill these cancers. The current proposal seeks to understand the mechanisms by which p53 and p63 regulate DNA repair in human keratinocytes during normal physiology, and to determine their role in the genesis and behavior of non-melanoma skin cancers. We hypothesize that p53 and p63 coordinately regulate repair of the major UVR-induced DNA photoproducts in both undifferentiated and terminally differentiating keratinocytes, and that dysregulation of this process occurs in squamous cell carcinomas and provides a mechanism for mutagenesis and tumor progression that may be therapeutically exploitable. The hypotheses will be tested by the following Specific Aims: 1) To determine the mechanisms by which p53 and p63 regulate repair protein levels in keratinocytes; 2) To determine the role of p63 in nucleotide excision repair during keratinocyte differentiation; 3) To assess the response of nucleotide excision repair to p63 over-expression in keratinocytes; and 4) To model, characterize and correct p63-mediated repair dysregulation in squamous cell carcinomas. At its conclusion, this project will elucidate the molecular basis of the unique photoprotective mechanisms of epidermal skin cells, allow us to understand how these mechanisms are dysfunctional during skin carcinogenesis, and suggest new strategies for preventing and treating skin cancers. PUBLIC HEALTH RELEVANCE: Project Narrative This project is significant for the health of veterans for the following reasons: 1) Sun-induced skin cancer is a considerable burden on veterans and VA. Skin cancers are the most prevalent malignancy in the United States, significantly affect quality of life are among the most costly of all cancers to treat. These cancers will continue to be a significant issue for VA in the future. 2) The DNA repair system studied also repairs other relevant DNA damage particular to military personnel and veterans, such as DNA lesions from heavy metals and from organic compounds from burning materials. 3) DNA damage and the response of the p53 family arise in other organ systems and injuries and are important in wound healing and other tissues' responses to ischemic or other physical trauma that are significant issues currently deployed troops who will be the veterans of the future. 4) A mechanistic understanding of skin cancer may lead to more specific medical treatments for skin cancer that avoid the morbidity, travel and cost of surgery.

描述（由申请人提供）： 项目摘要/摘要非黑色素瘤皮肤癌是美国普通人群中最常见的恶性肿瘤，并且在退伍军人群体中非常普遍。虽然这些皮肤癌通常不会致命，但它们可能是发病的主要来源，损害生活质量并占用大量的医疗保健资源。表皮角质形成细胞中的累积 DNA 损伤，尤其是太阳紫外线辐射造成的损伤，是非黑色素瘤皮肤癌发生的一个重要因素。此外，某些针对其他皮肤病的疗法会使用 DNA 损伤剂，从而增加患皮肤癌的风险。庞大的、扭曲的 DNA 损伤通过核苷酸切除修复过程被去除，但人们对角质形成细胞中 DNA 修复的调节知之甚少。临床观察和最近的体外研究（包括 PI 实验室的研究）表明，人类角​​质形成细胞具有调节核苷酸切除修复的独特机制。非角质形成细胞类型中肿瘤抑制因子 p53 的缺失通常会导致最丰富的 UVR 诱导光产物的修复丧失。然而，当前奖励期间的工作证明，角质形成细胞需要同时失去 p53 和该家族的另一个成员 - p63，才能修复受损。此外，PI 实验室最近的工作表明，p53 和 p63 的双重缺陷与鳞状细胞癌中核苷酸切除修复受损有关，可以利用这种修复来优先杀死这些癌症。目前的提案旨在了解 p53 和 p63 在正常生理过程中调节人类角质形成细胞 DNA 修复的机制，并确定它们在非黑色素瘤皮肤癌的发生和行为中的作用。我们假设 p53 和 p63 协调调节未分化和终末分化角质形成细胞中主要 UVR 诱导的 DNA 光产物的修复，并且该过程的失调发生在鳞状细胞癌中，并提供了一种可能在治疗上可利用的突变发生和肿瘤进展机制。 。这些假设将通过以下具体目标进行检验： 1) 确定 p53 和 p63 调节角质形成细胞中修复蛋白水平的机制； 2) 确定p63在角质形成细胞分化过程中核苷酸切除修复中的作用； 3) 评估核苷酸切除修复对角质形成细胞中p63过表达的反应； 4) 模拟、表征和纠正鳞状细胞癌中 p63 介导的修复失调。最后，该项目将阐明表皮皮肤细胞独特的光保护机制的分子基础，让我们了解这些机制在皮肤癌发生过程中如何发挥功能，并提出预防和治疗皮肤癌的新策略。 公共卫生相关性： 项目叙述 该项目对退伍军人的健康意义重大，原因如下： 1) 阳光诱发的皮肤癌对退伍军人和退伍军人事务部来说是一个相当大的负担。皮肤癌是美国最常见的恶性肿瘤，严重影响生活质量，是所有癌症中治疗费用最高的癌症之一。这些癌症未来仍将是退伍军人管理局面临的一个重大问题。 2）所研究的DNA修复系统还可以修复军事人员和退伍军人特有的其他相关DNA损伤，例如重金属和燃烧材料有机化合物造成的DNA损伤。 3) DNA损伤和p53家族的反应出现在其他器官系统和损伤中，对于伤口愈合和其他组织对缺血或其他身体创伤的反应很重要，这些是当前部署的部队（未来将成为退伍军人）面临的重大问题。 4) 对皮肤癌的机制了解可能会导致针对皮肤癌的更具体的医学治疗，从而避免发病率、旅行和手术费用。