ROLE OF P53 IN UV IMMUNE SUPPRESSION AND CARCINOGENESIS

联合国慢性照射诱发近交系小鼠皮肤癌的研究 具有抗原性，并显示高频率的P53突变。在这个模型中， 紫外线辐射诱发癌症的同时伴随着对 针对这些皮肤癌的免疫反应和免疫抑制 在皮肤癌的生长和发病机制中起着至关重要的作用。近期 研究表明，紫外线诱导的DNA损伤是 会引发免疫抑制。因为P53在这一过程中起着关键作用。 对DNA损伤的反应和修复，这个基因可能是必不可少的 在导致紫外线诱导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外。 此外，突变型p53蛋白可能与这种异常的抗原性有关。 紫外线诱导的肿瘤所表现出的特性。 为了检验这些假说，第53页剔除了老鼠，在这些老鼠中，有一个或两个拷贝 的P53基因已经被同源重组失活，将被 暴露在紫外线辐射下，并测试对紫外线诱导的敏感性 抑制细胞免疫和诱导免疫抑制 表皮细胞因子。将评估P53在紫外线致癌中的作用 通过比较C57BL/6基因对+/+、+/-和-/-小鼠的肿瘤诱导作用 背景资料。确定突变型P53蛋白是否作为一种 紫外线诱导肿瘤移植抗原的抗原性研究 我们将对+/+、+/-和-/-小鼠诱发的肿瘤进行比较。如果所有的肿瘤 在p53基因缺失的小鼠中诱导不表达紫外线相关的肿瘤抗原，这些 肿瘤将被用作突变的P53的转染体，以 确定突变型p53基因的导入和表达是否会导致 这些细胞具有紫外线诱导皮肤的异常抗原性 癌症。

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.