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Originally published as MBC in Press, 10.1091/mbc.01-11-0529 on April 24, 2002
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Vol. 13, Issue 7, 2502-2517, July 2002

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

Daniela Volonte,* Kun Zhang,* Michael P. Lisanti,dagger Dagger and Ferruccio Galbiati*§

 *Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261;  dagger Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461; and  Dagger The Division of Hormone-Dependent Tumor Biology, The Albert Einstein Cancer Center, Bronx, New York 10461

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 G0/G1 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.

§ Corresponding author. E-mail address: feg5{at}pitt.edu.

Molecular Biology of the Cell
Vol. 13, 2502-2517, July 2002
Copyright © 2002 by The American Society for Cell Biology


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