ROLE OF P53 IN UV IMMUNE SUPPRESSION AND CARCINOGENESIS

P53 在紫外线免疫抑制和致癌作用中的作用

• 批准号: 6311539
• 负责人: MARGARET L KRIPKE
• 金额: $ 15.02万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-21 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311539
• 关键词: DNA binding protein; DNA damage; cellular immunity; cellular oncology; cytokine; gene frequency; gene mutation; gene targeting; immunoprecipitation; immunosuppression; laboratory mouse; neoplastic growth; neoplastic process; polymerase chain reaction; protein structure function; radiation carcinogenesis; single strand conformation polymorphism; site directed mutagenesis; skin neoplasms; southern blotting; tissue /cell culture; transfection; tumor antigens; tumor suppressor genes; ultraviolet radiation

Skin cancers induced in inbred mice by chronic UN irradiation are highly antigenic and exhibit a high frequency of p53 mutations. In this model, cancer induction by UV radiation is accompanied by suppression of the immune response against these skin cancers, and the immune suppression plays an essential role in skin cancer growth and pathogenesis. Recent studies indicate the UV-induced DNA damage is the primary event that initiates immunosuppression. Because p53 plays a pivotal role in the response to and repair of DNA damage, this gene may serve as an essential control point in the pathway leading to UV-induced immune suppression, in addition to playing a role in the process of neoplastic transformation. Furthermore, mutant p53 protein could contribute to the unusual antigenic properties exhibited by UV-induced tumors. To test these hypotheses, p 53 knock out mice, in which one or both copies of th p53 gene have been inactivated by homologous recombination, will be exposed to UV radiation and tested for susceptibility to UV-induced suppression of cell-mediated immunity and induction of immunosuppressive epidermal cytokines. The role of p53 in UV carcinogenesis will be assessed by comparing tumor induction in +/+, +/-, and -/- mice on a C57BL/6 genetic background. To determine whether mutant p53 protein serves as a transplantation antigen on UV-induced tumors, the antigenic properties of tumors induced in +/+, +/-, and -/- mice will be compared. If athe tumors induced in p53 null mice do not express UV-associated tumor antigens, these tumors will be used as recipients for transfection of mutated p53, to determine whether introduction and expression of mutated p53 confers on these cells the unusual antigenic characteristics of UV-induced skin cancers.

慢性UN照射诱发近交系小鼠皮肤癌的发生率较高， 抗原性，并表现出高频率的p53突变。 在这个模型中， 紫外线辐射的癌症诱导伴随着抑制 针对这些皮肤癌的免疫反应以及免疫抑制 在皮肤癌的生长和发病机制中起重要作用。 最近 研究表明，紫外线诱导的DNA损伤是主要事件， 启动免疫抑制。 因为p53在细胞凋亡中起着关键作用， 对DNA损伤的反应和修复，该基因可能是一个必不可少的 在导致UV诱导的免疫抑制的途径中的控制点， 除了在肿瘤转化过程中发挥作用之外。 此外，突变型p53蛋白可能有助于不寻常的抗原性， UV诱导的肿瘤所表现出的特性。 为了验证这些假设，p53基因敲除小鼠，其中一个或两个拷贝 p53基因的同源重组失活， 暴露于UV辐射并测试对UV诱导的 抑制细胞介导免疫和诱导免疫抑制 表皮细胞因子 将评估p53在紫外线致癌作用中的作用。 通过比较C57 BL/6基因上+/+、+/-和-/-小鼠中的肿瘤诱导， 背景 为了确定突变型p53蛋白是否作为一种 移植抗原对紫外线诱导的肿瘤的抗原特性， 比较在+/+、+/-和-/-小鼠中诱导的肿瘤。 如果肿瘤 诱导的p53基因敲除小鼠不表达UV相关的肿瘤抗原，这些 肿瘤将被用作突变的p53转染的受体， 确定突变的p53的引入和表达是否赋予 这些细胞具有紫外线诱导皮肤的不寻常抗原特征 癌的