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，美国每年约有100万新诊断病例。这些肿瘤中的绝大多数是暴露在阳光下的结果，特别是紫外线B(UVB)辐射。越来越清楚的是，细胞周期调节因子，包括细胞周期蛋白Dl，是UVB诱导损伤的潜在目标。我们证明，UVB照射缺乏功能性P53的转化角质形成细胞株会导致GI细胞周期停滞。这种停滞与细胞周期蛋白D1和CDK4蛋白的降解相吻合，并且在一定程度上依赖于蛋白酶体。这表明，细胞对UVB辐射的早期反应是对细胞周期蛋白DL稳定性的调节。此外，在各种类型的肿瘤中都发现了细胞周期蛋白Dl水平的升高。事实上，我们在小鼠模型上进行的完整的光致癌研究表明，在UVB诱导的皮肤癌发生过程中，细胞周期蛋白DL蛋白的早期积累逐渐增加。因此，对细胞周期蛋白Dl稳定性的调节似乎是对UVB辐射的短期和长期反应的关键事件。我们建议在U-JB辐射后的细胞系和小鼠皮肤光癌模型中研究细胞周期蛋白Dl稳定性的调节机制。我们将验证一种假设，即在长期暴露于紫外线下的皮肤中，负责紫外线诱导的细胞周期蛋白DL快速降解的机制(S)受到损害，从而参与细胞周期蛋白DL的积聚，从而导致皮肤肿瘤的形成。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生的分子基础。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.