Role of Caveolin-1 in Cellular Senescence and Aging

点击翻译按钮获取中文摘要

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.