Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts - Stress-induced premature senescence upregulates the expression of endogenous caveolin-1
Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts - Stress-induced premature senescence upregulates the expression of endogenous caveolin-1
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DOI：
10.1091/mbc.01-11-0529
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发表时间：
2002-07-01
影响因子：
3.3
通讯作者：
Galbiati, F
中科院分区：
文献类型：
--
作者：
Volonte, D;Zhang, K;Galbiati, F
小窝是质膜上的囊泡内陷。小窝蛋白-1是小窝在体内的主要结构成分。有几条证据与小窝蛋白-1起“转化抑制”蛋白作用的观点是一致的。事实上，在细胞转化过程中，由于癌基因的激活，小窝蛋白-1mRNA和蛋白的表达会丢失或降低。有趣的是，人类小窝蛋白-1基因定位于一个可疑的肿瘤抑制基因(7q31.1)。我们先前已经证明，小窝蛋白-1的过表达通过激活依赖于p53/p21的通路将小鼠胚胎成纤维细胞阻滞在细胞周期的G(0)/G(1)期，表明小窝蛋白-1在介导生长停滞中发挥了作用。然而，目前尚不清楚在体内过表达小窝蛋白-1是否会促进细胞衰老。在这里，我们证明了转基因过表达小窝蛋白-1的小鼠胚胎成纤维细胞表现出：1)增殖寿命缩短；2)衰老样细胞形态；以及3)与衰老相关的β-半乳糖苷酶活性增加。这些结果首次表明小窝蛋白-1在体内的表达足以促进和维持衰老表型。亚细胞毒性氧化应激可诱导二倍体成纤维细胞提前衰老。有趣的是，我们发现亚细胞毒性水平的过氧化氢诱导NIH3T3细胞提前衰老，并增加内源性小窝蛋白-1的表达。重要的是，槲皮素和维生素E这两种抗氧化剂成功地阻止了过氧化氢诱导的早衰表型和小窝蛋白-1的上调。此外，我们还证明了过氧化氢单独，而不是与槲皮素联合使用，可以刺激小凹蛋白-1启动子的活性。有趣的是，在含有反义小窝蛋白-1的NIH3T3细胞中，过氧化氢诱导的早衰大大减少。重要的是，当小窝蛋白-1水平恢复时，早衰的诱导就会恢复。综上所述，这些结果清楚地表明了小窝蛋白-1在促进细胞衰老中的中心作用，并提出了一种假说，即过早衰老可能代表了小窝蛋白-1在体内介导的肿瘤抑制功能。
Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1 is the principal structural component of caveolae in vivo. Several lines of evidence are consistent with the idea that caveolin-1 functions as a "transformation suppressor" protein. In fact, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). We have previously demonstrated that overexpression of caveolin-1 arrests mouse embryonic fibroblasts in the G(0)/G(1) phase of the cell cycle through activation of a p53/p21-dependent pathway, indicating a role of caveolin-1 in mediating growth arrest. However, it remains unknown whether overexpression of caveolin-1 promotes cellular senescence in vivo. Here, we demonstrate that mouse embryonic fibroblasts transgenically overexpressing caveolin-1 show: 1) a reduced proliferative lifespan; 2) senescence-like cell morphology; and 3) a senescence-associated increase in beta-galactosiclase activity. These results indicate for the first time that the expression of caveolin-1 in vivo is sufficient to promote and maintain the senescent phenotype. Subcytotoxic oxidative stress is known to induce premature senescence in diploid fibroblasts. Interestingly, we show that subcytotoxic level of hydrogen peroxide induces premature senescence in NIH 3T3 cells and increases endogenous caveolin-1 expression. Importantly, quercetin and vitamin E, two antioxidant agents, successfully prevent the premature senescent phenotype and the up-regulation of caveolin-1 induced by hydrogen peroxide. Also, we demonstrate that hydrogen peroxide alone, but not in combination with quercetin, stimulates the caveolin-1 promoter activity. Interestingly, premature senescence induced by hydrogen peroxide is greatly reduced in NIH 3T3 cells harboring antisense caveolin-1. Importantly, induction of premature senescence is recovered when caveolin-1 levels are restored. Taken together, these results clearly indicate a central role for caveolin-1 in promoting cellular senescence and they suggest the hypothesis that premature senescence may represent a tumor suppressor function mediated by caveolin-1 in vivo.