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

描述（由申请人提供）：衰老的表现之一是细胞和有机体水平上损伤的积累。基因毒性应激在衰老和年龄相关疾病（如肺气肿）中发挥重要作用，肺气肿是由持续氧化应激后肺维持和修复功能失败引起的。香烟烟雾是氧化剂的一种来源，被认为是导致肺气肿的环境危害。过早衰老被认为有助于基因毒性应激诱导的肺气肿。肿瘤抑制蛋白p53是过早衰老的关键调控因子，当ATM抑制剂蛋白磷酸酶2A （PP2A）在基因毒性应激后与ATM分离时，p53被ATM蛋白激酶激活。基因毒性应激下ATM中PP2A-C去除的机制仍未完全探索。此外，ATM/p53通路在香烟引起的细胞衰老和肺气肿的发病机制中所起的作用仍不清楚。在这里，我们计划验证脂质筏蛋白caveolin-1通过将ATM抑制剂PP2A-C隔离到小泡中，促进ATM依赖的p53激活，从而介导应激诱导的过早衰老的假设。此外，有假设认为caveolin-1通过诱导细胞衰老在体内氧化促进的肺气肿中起核心作用。这一假设将通过追求三个特定目标来验证：特定目标1：研究caveolin-1在基因毒性应激后pp2a介导的ATM功能调节中的作用。特异性目的2：确定caveolin-1表达缺失对atm介导的p53激活和过早衰老的功能影响。特异性目的3：确定小泡蛋白-1在体内基因毒性应激性肺气肿中的作用。这些研究将为基因毒性应激与细胞衰老之间的信号机制提供新的见解，并提出小泡蛋白-1作为治疗肺气肿等年龄相关疾病的新治疗靶点。公共卫生相关性：氧化应激，包括吸烟，促进细胞过早衰老，这被认为在更复杂的衰老过程中起重要作用，并导致与年龄有关的疾病，如肺气肿。香烟引起的肺气肿的分子机制尚不完全清楚。我们的研究将验证caveolin-1蛋白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caveolin-1作为治疗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.