Cell cycle regulatory proteins in UVB-skin carcinogenes

描述（由申请人提供）： 基底细胞癌和鳞状细胞癌（非黑色素瘤皮肤癌或NMSC）是最常见的人类恶性肿瘤类型，在美国每年诊断出约100万新发病例。这些肿瘤中的绝大多数是暴露于阳光，特别是紫外线B（UVB）辐射的结果。越来越清楚的是，细胞周期调节因子，包括细胞周期蛋白D1，是UVB诱导的损伤的潜在靶点。我们证明，UVB照射的转化角质形成细胞系缺乏功能性p53的结果在GI细胞周期停滞。这种逮捕与细胞周期蛋白D1和cdk4蛋白的降解相一致，并且部分依赖于蛋白酶体。这表明细胞周期蛋白D1蛋白稳定性的调节是对UVB辐射的早期细胞反应。此外，在各种类型的肿瘤中发现细胞周期蛋白D1水平增加。事实上，我们在小鼠模型中进行的完整的光致癌研究表明，在UVB诱导的皮肤致癌过程中，细胞周期蛋白D1蛋白的早期积累逐渐增加。因此，调节细胞周期蛋白D1的稳定性似乎是UVB辐射的短期和长期反应的关键事件。我们建议研究调节细胞周期蛋白D1的稳定性的机制后，U\JB辐射在细胞系和小鼠皮肤光致癌模型。我们将检验这样的假设，即负责UVB诱导的细胞周期蛋白D1快速降解的机制在长期暴露于UVB的皮肤中受损，从而参与细胞周期蛋白D1的积累，导致皮肤肿瘤形成。我们预计，体外和体内方法的结合将有助于更好地了解皮肤癌发展的分子基础。此外，我们的研究可以为开发针对蛋白质降解机制的新治疗工具提供理论基础。

DESCRIPTION (provided by applicant): Basal Cell and squamous cell carcinomas (nonmelanoma skin cancers or NMSC) are the most common type of human malignancies with approximately one million new cases diagnosed annually in the United States. The vast majority of these tumors are the result of exposure to sunlight, particularly ultraviolet B (UVB) radiation. It is becoming increasingly clear that cell cycle regulators, including cyclin Dl, are potential targets for UVB-induced damages. We demonstrated that UVB irradiation of a transformed keratinocyte cell line lacking functional p53 results in cell cycle arrest in GI. This arrest coincided with the degradation of cyclin Dl and cdk4 proteins and was, in part, proteasome-dependent. This suggests that regulation of cyclin Dl protein stability is an early cellular response to UVB radiation. Furthermore, increased levels of cyclin Dl are found in various types of tumors. Indeed, our complete photocarcinogenesis study in a mouse model showed the early accumulation of cyclin Dl protein that increased gradually during UVB-induced skin carcinogenesis. Thus, regulation of cyclin Dl stability seems to be a key event of the short- and long-term responses to UVB radiation. We propose to study the mechanisms regulating cyclin Dl stability following U\JB radiation in cell lines and in mouse models for skin photocarcinogenesis. We will test the hypothesis that the mechanism(s) responsible for the rapid UVB-induced degradation of cyclin Dl are impaired in skin chronically exposed to UVB, thus participating in the accumulation of cyclin Dl leading to skin tumors formation. We anticipate that the combination of in vitro and in vivo approaches will help to better understand the molecular basis of skin cancer development. In addition, our studies could provide a rationale to develop new therapeutic tools targeted towards the protein degradation machinery.