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Vol. 12, Issue 8, 2229-2244, August 2001
§ and
*Department of Molecular Pharmacology and The Albert Einstein
Cancer Center, Albert Einstein College of Medicine, Bronx, New York
10461; Caveolin-1 is a principal component of caveolae membranes in vivo.
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). However, it remains unknown whether caveolin-1 plays any role
in regulating cell cycle progression. Here, we directly demonstrate
that caveolin-1 expression arrests cells in the
G0/G1 phase of the cell cycle. We show that
serum starvation induces up-regulation of endogenous caveolin-1 and
arrests cells in the G0/G1 phase of the cell
cycle. Moreover, targeted down-regulation of caveolin-1 induces cells
to exit the G0/G1 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 that recombinant expression of Cav-1-GFP induces arrest in
the G0/G1 phase of the cell cycle. To examine whether caveolin-1 expression is important for modulating cell cycle
progression in vivo, we expressed wild-type caveolin-1 as a transgene
in mice. Analysis of primary cultures of mouse embryonic fibroblasts from caveolin-1 transgenic mice reveals that
caveolin-1 induces 1) cells to exit the S phase of the cell cycle with
a concomitant increase in the G0/G1 population,
2) a reduction in cellular proliferation, and 3) a reduction in the DNA
replication rate. Finally, we demonstrate that caveolin-1-mediated cell
cycle arrest occurs through a p53/p21-dependent pathway. Taken
together, our results provide the first evidence that caveolin-1
expression plays a critical role in the modulation of cell cycle
progression in vivo.
Departments of Developmental and Molecular
Biology and The Albert Einstein Cancer Center, Albert Einstein College
of Medicine, Bronx, New York 10461; and §Department of
Medicine, Albert Einstein College of Medicine, Bronx, New York 10461
Current address: The University of
Pittsburgh School of Medicine, Department of Pharmacology, Biomedical
Science Tower (BST) West, Room 1302, Pittsburgh, PA 15261-0001.
Corresponding author. E-mail address:
lisanti{at}aecom.yu.edu.
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