Caveolin-1 expression negatively regulates cell cycle progression by inducing G(0)/G(1) arrest via a p53/p21(WAF1/Cip1)-dependent mechanism

Caveolin-1 is a principal component of caveolae membranes in vivo. Caveolin -1 mRNA and protein expression are lost or reduced during cell transformati on by activated oncogenes. Interestingly, the human caveolin-1 gene is loca lized to a suspected tumor suppressor locus (7q31.1). However, it remains u nknown whether caveolin-1 plays any role in regulating cell cycle progressi on. Here, we directly demonstrate that caveolin-1 expression arrests cells in the G(0)/G(1) phase of the cell cycle. We show that serum starvation ind uces up-regulation of endogenous caveolin-1 and arrests cells in the G(0)/G (1) phase of the cell cycle. Moreover, targeted down-regulation of caveolin -1 induces cells to exit the G(0)/G(1) phase. Next, we constructed a green fluorescent protein-tagged caveolin-1 (Cav-1-GFP) to examine the effect of caveolin-1 expression on cell cycle regulation. We directly demonstrate tha t recombinant expression of Cav-1-GFP induces arrest in the G(0)/G(1) phase of the cell cycle. To examine whether caveolin-1 expression is important f or modulating cell cycle progression in vivo, we expressed wild-type caveol in-1 as a transgene in mice. Analysis of primary cultures of mouse embryoni c fibroblasts from caveolin-1 transgenic mice reveals that caveolin-1 induc es 1) cells to exit the S phase of the cell cycle with a concomitant increa se in the G(0)/G(1) population, 2) a reduction in cellular proliferation, a nd 3) a reduction in the DNA replication rate. Finally, we demonstrate that caveolin-1-mediated cell cycle arrest occurs through a p53/p21-dependent p athway. Taken together, our results provide the first evidence that caveoli n-1 expression plays a critical role in the modulation of cell cycle progre ssion in vivo.