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-galactosidase 
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.