Role of Caveolin-1 in Cellular Senescence and Aging

Caveolin-1 在细胞衰老中的作用

• 批准号: 6999304
• 负责人: FERRUCCIO GALBIATI
• 金额: $ 25.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999304
• 关键词: DNA binding protein; biological signal transduction; caveolas; caveolins; cell cycle; cell senescence; gel mobility shift assay; genetic regulatory element; inhibitor /antagonist; intracellular transport; laboratory mouse; membrane activity; membrane proteins; northern blottings; nuclear factor kappa beta; oxidative stress; p53 gene /protein; polymerase chain reaction; protein degradation; protein structure function; proteolysis; proteomics; transcription factor; transfection

One of the manifestations of aging is the accumulation of damage at both cellular and organism levels. This damage is initiated by endogenous and exogenous stimuli, including oxidative stress. Interestingly, reactive oxygen species have been shown to promote premature cellular senescence in culture, which is believed to have an important role in the more complicated ageing process. Caveolin-1 is the structural component of caveolae and is used by the cell to compartmentalize and functionally regulate signaling molecules. We have recently demonstrated that over-expression of caveolin-1 is sufficient to arrest mouse embryonic fibroblasts in the G0/G1 phase of the cell cycle and induce premature cellular senescence. However, whether caveolin-1 is a central figure in promoting cellular senescence remains unknown. In this proposal, we plan to test the hypothesis that caveolin-1 represents a key player in oxidative stress-induced premature senescence (SIPS). The three long-term objectives of this proposal are: 1. To characterize the caveolin-1 promoter response to oxidative stress. 2. To investigate modulation of the p53 pathway by caveolin-1 in SIPS. 3. To identify signaling molecules that are enriched into caveolar membranes after oxidative stress. In order to characterize the caveolin-1 promoter response to oxidative stress, we propose to identify the transcription factors that stimulate caveolin-1 gene expression during the cellular response to oxidative stress. To investigate modulation of the p53 pathway by caveolin-1 we will test the hypothesis that caveolin-1 activates p53 by sequestering Mdm-2 into caveolar membranes. To identify signaling molecules that are enriched into caveolar membranes after oxidative stress, we plan to use a proteomic-based approach to clone and characterize signaling molecules that move into caveolae upon oxidant stimulation. Understanding the signal transduction machinery involved in oxidative stress-induced premature senescence will provide new insights into the free radical theory of aging.

衰老的表现之一是在细胞和生物体水平上均积累损伤。 这种损害是由内源性和外源刺激（包括氧化应激）引发的。有趣的是，活性氧已被证明可以促进培养物中的过早细胞衰老，这被认为在更复杂的衰老过程中具有重要作用。 Caveolin-1是Caveolae的结构成分，细胞用于分隔和功能调节信号分子。我们最近证明，小窝蛋白-1的过表达足以使小鼠胚胎成纤维细胞在细胞周期的G0/G1期间诱导过早的细胞衰老。然而，小窝蛋白1是否是促进细胞衰老的中心数字仍然未知。 在该提案中，我们计划检验以下假设：小窝蛋白-1代表氧化应激诱导的早衰老（SIPS）的关键参与者。 该提案的三个长期目标是：1。表征小窝蛋白-1启动子对氧化应激的反应。 2。研究小窝1中小窝蛋白1对p53途径的调节。 3。鉴定氧化应激后富集到洞穴膜中的信号分子。 为了表征小窝蛋白-1启动子对氧化应激的反应，我们建议在细胞对氧化应激的反应过程中识别刺激小窝蛋白-1基因表达的转录因子。 为了研究Caveolin-1对p53途径的调节，我们将测试Caveolin-1通过将MDM-2隔离为小窝膜来激活p53的假设。为了鉴定氧化应激后富集到小窝膜中的信号分子，我们计划使用基于蛋白质组学的方法克隆并表征信号分子在氧化剂刺激后转移到caveolae中的信号分子。 了解参与氧化应激引起的过早衰老的信号转导机制将为自由基衰老理论提供新的见解。