Bid regulation of cutaneous photodamage responses

皮肤光损伤反应的投标调节

• 批准号: 7740500
• 负责人: Laura Timares
• 金额: $ 13.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740500
• 关键词: Apoptosis; Apoptotic; Ataxia-Telangiectasia-Mutated protein kinase; Biochemical; Cancer Control; Carcinogens; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Death; Cell Line; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cellular Stress; Cessation of life; Cutaneous; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; Data; Development; Diagnostic; Equilibrium; Event; Exhibits; Family member; Fibroblasts; Future; Genetic; Hand; Homeostasis; Human; In Vitro; Knock-out; Lead; Length; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Mitochondria; Molecular; Mus; Mutate; Mutation; Myeloid Progenitor Cells; Oncogenic; Pathway interactions; Peptide Hydrolases; Phase; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Protein Isoforms; Protein p53; Proteins; Reagent; Receptor Activation; Receptor Signaling; Recovery; Regulation; Role; Sentinel; Signal Transduction; Skin; Skin Carcinogenesis; Squamous cell carcinoma; TP53 gene; Techniques; Testing; The Sun; Therapeutic; Time; Tumor Suppression; Tumor Suppressor Proteins; UV induced; Ultraviolet B Radiation; Ultraviolet Rays; Wild Type Mouse; Wound Healing; carcinogenesis; caspase-8; cell injury; keratinocyte; keratinocyte differentiation; mouse model; mutant; novel; public health relevance; receptor; reconstitution; repaired; research study; response; sensor; tumor; tumorigenic; ultraviolet; ultraviolet damage; ultraviolet irradiation

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.

描述（由申请人提供）： 光损伤反应起着针对皮肤癌症发展的保护作用。它通过恢复较轻的细胞来策划组织修复，同时消除具有致癌潜力的突变细胞。细胞传感器有望响应不同水平的紫外线诱导的损伤来推进DNA修复途径或凋亡级联反应。从恢复细胞中整合细胞信号并决定其命运的分子尚未完全了解。光损伤反应的潜在重要调节剂是Bcl-2，“仅BH3”家庭成员，BID。出价是凋亡线粒体途径的众所周知的引发剂。矛盾的是，竞标还具有通过激活S期间细胞周期检查点的细胞恢复功能来恢复细胞的功能。这些相反的活性是通过出价的截然不同的翻译后修饰（一种磷酸化形式（PBID），该修饰作用于核或针对线粒体的截短形式（TBID）（TBID）。投标的双重函数与肿瘤抑制剂p53具有一定的相似性，肿瘤p53是细胞命运的最著名调节剂。我们已经确定，紫外线辐射可以在小鼠和人皮细胞中诱导生存形式，pbid。此外，我们有证据表明竞标是肿瘤抑制因子。在表皮对紫外线照射的反应中尚未确定投标在促进细胞存活中的作用。该提案将检验以下假设，即通过促进DNA修复或细胞凋亡，出价在角质形成细胞UVB光损伤反应中起关键作用。我们将确定PBID在小鼠和人类细胞中执行S期检查点函数的程度。此外，我们将评估UV-DNA损伤激酶ATR的作用，以及p53在调节投标函数中的作用。我们将检查出价不足细胞的致瘤潜力，以及与WT和突变形式重构的细胞，以确定其肿瘤抑制活性映射到细胞存活或凋亡功能。我们还将创建一个新的小鼠模型，以评估BID在鳞状细胞癌发展中作为肿瘤抑制器的作用。具体目的如下：1。确定投标在促进UVB损坏的皮肤细胞中DNA修复中的作用。 2。确定投标缺乏对紫外线诱导的皮肤肿瘤发展的影响。公共卫生相关性：来自太阳的紫外线（UV）是一种有效的致癌物，因为它在DNA中引入突变并造成细胞损伤。我们将研究一种称为BID的分子表现出的新型肿瘤抑制功能，具体侧重于其在细胞周期检查点活性中的作用，该作用被UV辐射激活，及其在抑制UV诱导的肿瘤发展中的作用。这些研究的结果可能会发现一种用于控制癌症的新机制，也可能是诊断或治疗应用的新目标。