Caveolin 1: a novel modulator of the PP2A/ATM/p53 pathway

描述(申请人提供)：衰老的表现之一是在细胞和机体水平上的损害的积累。遗传毒性应激在衰老和老年相关疾病如肺气肿中起着重要作用，肺气肿是由于持续氧化应激后肺的维护和修复失败而引起的。香烟烟雾是氧化剂的来源之一，被认为是导致肺气肿的环境危害。早衰被认为是遗传毒性应激引起的肺气肿的原因之一。抑癌蛋白P53是早衰的关键调节因子，当ATM抑制蛋白磷酸酶2A(PP2A)在基因毒性应激后从ATM中解离出来时，该蛋白被ATM蛋白激酶激活。在基因毒性应激下，从ATM中去除PP2A-C的机制仍然完全不清楚。此外，ATM/P53通路在香烟烟雾诱导的细胞衰老和肺气肿的发病机制中所起的作用还很大程度上仍不清楚。在这里，我们计划验证这样的假设，即脂筏蛋白小窝蛋白-1通过将ATM抑制剂PP2A-C隔离到小窝中来促进ATM依赖的p53激活，从而介导应激诱导的早衰。此外，推测小窝蛋白-1通过诱导细胞衰老在体内氧化剂促进的肺气肿中起中心作用。这一假说将通过追求三个特定的目标来验证：特定的目标1：研究小窝蛋白-1在遗传毒性应激后PP2A介导的ATM功能调节中的作用。特定目的2：确定小窝蛋白-1表达缺失对ATM介导的P53激活和过早衰老的功能后果。具体目标3：明确小窝蛋白-1在体内遗传毒性应激诱导的肺气肿中的作用。这些研究将为将遗传毒性应激与细胞衰老联系起来的信号机制提供新的见解，并建议将小窝蛋白-1作为治疗年龄相关疾病(如肺气肿)的新靶点。公共卫生相关性：包括香烟烟雾在内的氧化应激会促进细胞过早衰老，这被认为在更复杂的衰老过程中起着重要作用，并导致与年龄相关的疾病，如肺气肿。香烟烟雾引起肺气肿的分子机制尚不完全清楚。我们的研究将验证蛋白质小窝蛋白-1是应激诱导的细胞衰老和肺气肿的新调节因子的假设，并提出小窝蛋白-1作为治疗诸如肺气肿等年龄相关疾病的替代治疗靶点。

DESCRIPTION (provided by applicant): One of the manifestations of aging is the accumulation of damage at both cellular and organism levels. Genotoxic stress plays an important role in aging and age-related diseases such as emphysema, which is caused by a failure of lung maintenance and repair after sustained oxidative stress. Cigarette smoke represents a source of oxidants and is considered an environmental hazard that causes pulmonary emphysema. Premature senescence is believed to contribute to genotoxic stress-induced emphysema. The tumor suppressor protein p53 is a key regulator of premature senescence and is activated by the ataxia-telangiectasia mutated (ATM) protein kinase when the ATM inhibitor protein phosphatase 2A (PP2A) dissociates from ATM after genotoxic stress. The mechanism underlying PP2A-C removal from ATM upon genotoxic stress remains totally unexplored. In addition, the role that the ATM/p53 pathway plays in cigarette smoke-induced cellular senescence and the pathogenesis of emphysema remains largely unknown. Here, we plan to test the hypothesis that the lipid raft protein caveolin-1 mediates stress-induced premature senescence by promoting ATM-dependent activation of p53 through sequestration of the ATM inhibitor PP2A-C into caveolae. In addition, it is hypothesized that caveolin-1 plays a central role in oxidant-promoted emphysema in vivo through induction of cellular senescence. This hypothesis will be tested by pursuing three specific aims: Specific Aim 1: Investigate the role of caveolin-1 in PP2A-mediated regulation of ATM function after genotoxic stress. Specific Aim 2: Determine the functional consequences of loss of caveolin-1 expression on ATM-mediated p53 activation and premature senescence. Specific Aim 3: Define the role of caveolin-1 in genotoxic stress-induced pulmonary emphysema in vivo. These studies will provide novel insights into the signaling machinery that links genotoxic stress to cellular senescence and propose caveolin-1 as a novel therapeutic target for the treatment of age-related diseases such as emphysema. PUBLIC HEALTH RELEVANCE: Oxidative stress, including cigarette smoke, promotes premature cellular senescence, which is believed to have an important role in the more complicated aging process, and contributes to age-related diseases like emphysema. The molecular mechanisms underlying cigarette smoke-induced emphysema are not fully understood. Our studies will test the hypothesis that the protein caveolin-1 is a novel regulator of stress-induced cellular senescence and emphysema, and propose caveolin-1 as an alternative therapeutic target for the treatment of age-related diseases such as emphysema.