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）： 非黑色素瘤皮肤癌是美国普通人群中最常见的恶性肿瘤，在退伍军人中非常普遍。虽然通常不致命，但这些皮肤癌可能是发病率的主要来源，损害生活质量，并占用大量的卫生保健资源。表皮角质形成细胞中的累积DNA损伤，特别是来自太阳紫外线辐射的损伤，是非黑色素瘤皮肤癌发展的重要因素。此外，用于其他皮肤病的某些疗法利用增加皮肤癌风险的DNA损伤剂。庞大的，扭曲的DNA损伤被删除的过程中的核苷酸切除修复，但鲜为人知的是，角质形成细胞中的DNA修复的调节。临床观察和最近的体外研究，包括来自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。在非角质形成细胞类型中肿瘤抑制因子p53的缺失通常导致最丰富的UVR诱导的光产物的修复的缺失。然而，在目前的研究中，角质形成细胞需要p53和另一个家族成员p63的缺失才能修复受损。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受损的核苷酸切除修复相关，这可能被用来优先杀死这些癌症。目前的建议旨在了解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协调调节修复的主要紫外线诱导的DNA光产物在未分化和终末分化的角质形成细胞，这一过程中发生失调的鳞状细胞癌，并提供了一种机制，诱变和肿瘤进展，可能是治疗利用。本研究的主要目的是：1）确定p53和p63调节角质形成细胞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）评估角质形成细胞中核苷酸切除修复对p63过表达的反应;和4）在鳞状细胞癌中建模、表征和校正p63介导的修复失调。在其结论中，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，使我们能够了解这些机制在皮肤癌发生过程中是如何功能失调的，并提出预防和治疗皮肤癌的新策略。 公共卫生关系： 该项目对退伍军人的健康具有重要意义，原因如下：1）阳光引起的皮肤癌对退伍军人和VA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。这些癌症将继续成为VA未来的一个重要问题。2)研究的DNA修复系统还修复了其他相关的DNA损伤，特别是军事人员和退伍军人，如重金属和燃烧材料中的有机化合物造成的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，并且在伤口愈合和其他组织对缺血性或其他物理创伤的反应中是重要的，这是目前部署的部队的重要问题，他们将成为未来的退伍军人。4)对皮肤癌的机械理解可能会导致更具体的皮肤癌治疗方法，从而避免手术的发病率，旅行和费用。