Bid regulation of cutaneous photodamage responses

描述（由申请人提供）： 光损伤反应对皮肤中的癌症发展起保护作用。它通过恢复轻度受损的细胞来协调组织修复，同时消除具有致癌潜力的突变细胞。细胞传感器准备推进DNA修复途径或凋亡级联反应，以应对不同水平的紫外线诱导的损伤。整合来自恢复细胞的细胞信号并决定其命运的分子尚未完全了解。光损伤反应的一个潜在的重要调节因子是Bcl-2，“BH 3-only”家族成员，Bid。Bid是众所周知的线粒体凋亡途径的启动子。巧合的是，Bid还具有通过在S期期间激活细胞周期检查点来促进细胞恢复的促存活功能。这些相反的活动是由Bid的明显不同的翻译后修饰完成的-磷酸化形式（pBid）在细胞核中起作用，或截短形式（tBid）靶向细胞核。Bid的双重功能与肿瘤抑制因子p53有一些相似之处，p53是最知名的细胞命运调节因子。我们已经确定，紫外线辐射可以诱导小鼠和人类皮肤细胞中的促生存形式pBid。此外，我们有证据表明Bid是一种肿瘤抑制因子。Bid在促进细胞存活中的作用尚未在表皮对UV照射的反应中确定。这个建议将测试的假设，投标起着至关重要的作用，角质形成细胞UVB光损伤反应，促进DNA修复或凋亡。我们将确定pBid在小鼠和人细胞中执行S期检查点功能的程度。此外，我们将评估UV-DNA损伤激酶ATR和p53在调节Bid功能中的作用。我们将研究Bid缺陷细胞以及用野生型和突变型Bid重建的细胞的致瘤潜力，以确定其肿瘤抑制活性是否映射到细胞存活或凋亡功能。我们还将建立一个新的小鼠模型，以评估Bid作为肿瘤抑制因子在鳞状细胞癌发展中的作用。具体目标如下：1.目的探讨Bid对UVB损伤皮肤细胞DNA修复的促进作用。2.确定Bid缺乏对UV诱导的皮肤肿瘤发生的影响。公共卫生相关性：来自太阳的紫外线（UV）是一种强效致癌物质，因为它会在DNA中引入突变并导致细胞损伤。我们将研究一种名为Bid的分子所表现出的新型肿瘤抑制功能，特别关注其在紫外线辐射激活的细胞周期检查点活性中的作用，以及其在抑制紫外线诱导的肿瘤发展中的作用。这些研究的结果可能揭示控制癌症的新机制，以及诊断或治疗应用的可能新靶点。

DESCRIPTION (provided by applicant): The photodamage response plays a protective role against cancer development in skin. It orchestrates tissue repair by recovering lightly damaged cells and at the same time eliminates mutated cells with oncogenic potential. Cellular sensors are poised to advance either DNA repair pathways or apoptosis cascades in response to different levels of UV-induced damage. The molecules that integrate the cellular signals from a recovering cell and decide its fate are not fully understood. A potentially important regulator of the photodamage response is the Bcl-2, "BH3-only" family member, Bid. Bid is a well-known initiator of the mitochondrial pathway of apoptosis. Paradoxically, Bid also possesses a prosurvival function for cell recovery by activating a cell cycle checkpoint during S-phase. These opposing activities are performed by distinctly different posttranslational modifications of Bid - a phosphorylated form (pBid) that acts in the nucleus or a truncated form (tBid) that targets the mitochondrion. The dual functions of Bid have some similarities to the tumor suppressor p53, the best-known regulator of cell fate. We have established that UV radiation can induce the prosurvival form, pBid, in mouse and human skin cells. Furthermore, we have evidence that Bid is a tumor suppressor. Bid's role in promoting cell survival has not been determined in the epidermal response to UV irradiation. This proposal will test the hypothesis that Bid plays a critical role in keratinocyte UVB photodamage responses by promoting either DNA repair or apoptosis. We will determine the extent to which pBid performs S-phase checkpoint function in both mouse and human cells. Further, we will evaluate the roles of the UV-DNA damage kinase ATR, and p53 in regulating Bid function. We will examine the tumorigenic potential of Bid deficient cells as well as cells reconstituted with both WT and mutant forms of Bid to determine whether its tumor suppressor activity maps to cell survival or apoptotic functions. We will also create a new mouse model to assess Bid's role as tumor suppressor in the development of squamous cell carcinoma. The specific aims are as follows: 1. To determine the role of Bid in promoting DNA repair in UVB damaged skin cells. 2. To determine the impact of Bid deficiency on the development of UV-induced cutaneous tumors. PUBLIC HEALTH RELEVANCE: Ultraviolet (UV) light from the sun is a potent carcinogen because it introduces mutations in the DNA and causes cell damage. We will investigate a novel tumor suppressor function exhibited by a molecule called Bid, with specific focus on its proposed role in cell-cycle checkpoint activity that is activated by UV radiation, and its role in suppressing the development of UV-induced tumors. The results from these studies may uncover a new mechanism for controlling cancer and a possible new target for diagnostic or therapeutic applications.