Caveolin-1 Expression Is Required for the Development of Pulmonary Emphysema through Activation of the ATM-p53-p21 Pathway
Caveolin-1 Expression Is Required for the Development of Pulmonary Emphysema through Activation of the ATM-p53-p21 Pathway
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DOI：
10.1074/jbc.c800225200
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发表时间：
2009-02-27
影响因子：
4.8
通讯作者：
Galbiati, Ferruccio
中科院分区：
文献类型：
--
作者：
Volonte, Daniela;Kahkonen, Beth;Galbiati, Ferruccio
自由基在衰老和与年龄相关的人类疾病（包括肺气肿）中发挥着作用。香烟烟雾是氧化剂的来源，被认为是导致肺气肿的环境危害。在这里，我们发现，caveolin-1 通过将 ATM 抑制剂（蛋白磷酸酶 2A 的催化亚基）隔离到小凹膜中，在氧化应激后激活毛细血管扩张共济失调突变 (ATM)。我们证明，香烟烟雾提取物会促进野生型应激诱导的早衰，但不会促进 Caveolin-1 缺失的肺成纤维细胞，并且在体外香烟烟雾提取物刺激后，Caveolin-1 的表达是激活 ATM-p53-p21(Waf1/Cip1) 通路所必需的。体内研究表明，caveolin-1 的表达对于吸烟引起的肺成纤维细胞衰老和肺气肿是必需的。这些发现为ATM-p53途径自由基激活的分子机制带来了新的见解，并表明caveolin-1是治疗和/或预防肺气肿的新治疗靶点。
Free radicals play a role in aging and age-related human diseases, including pulmonary emphysema. Cigarette smoke represents a source of oxidants and is considered an environmental hazard that causes pulmonary emphysema. Here, we show that caveolin-1 activates ataxia telangiectasia-mutated (ATM) after oxidative stress by sequestering the ATM inhibitor, the catalytic subunit of protein phosphatase 2A, into caveolar membranes. We demonstrate that cigarette smoke extracts promote stress-induced premature senescence in wild type but not caveolin-1 null lung fibroblasts and that caveolin-1 expression is required for activation of the ATM-p53-p21(Waf1/Cip1) pathway following stimulation with cigarette smoke extracts in vitro. In vivo studies show that caveolin-1 expression is necessary for cigarette smoking-induced senescence of lung fibroblasts and pulmonary emphysema. These findings bring new insights into the molecular mechanism underlying free radical activation of the ATM-p53 pathway and indicate that caveolin-1 is a novel therapeutic target for the treatment and/or prevention of pulmonary emphysema.