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Departments of Pharmacology (D.K., S.A.S., R.K.A.) and Medicine (D.J.R.) and Center for Experimental Therapeutics (E.M.S.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Wistar Institute, Philadelphia, Pennsylvania (I.A., E.P.); and The Ludwig Institute for Cancer Research, New York, New York (E.P.)
The prostanoid prostacyclin (PGI2) inhibits aortic smooth muscle cell proliferation by blocking cell cycle progression from G1-to S-phase. However, the mechanism of this inhibition is poorly understood. We report here that the PGI2 mimetic, cicaprost, inhibits the induction of cyclin A and activation of the cyclin A promoter in primary and established rodent aortic smooth muscle cells. The inhibition of cyclin A gene expression is associated with a block in cyclin E-cdk2 activity and phosphorylation of both the retinoblastoma protein and p107. Inactivation of pocket proteins with human papilloma virus protein E7 partially, but not completely, restored cyclin A promoter activity in cicaprost-treated cells. Complementary studies showed that occupancy of the cAMP response element (CRE) is required for efficient activation of the cyclin A promoter in aortic smooth muscle cells, that the CRE is primarily occupied by the CRE-binding protein (CREB) and phospho-CREB, and that cicaprost blocks the binding of CREB and phospho-CREB to the cyclin A promoter CRE. Treatment with pertussis toxin reversed the inhibitory effects of cicaprost on CRE occupancy, cyclin E-cdk2 activity, and S phase entry, suggesting the involvement of Gi signaling in cicaprost action. We conclude that PGI2 inhibits proliferation of aortic smooth muscle cells by coordinately blocking CRE- and pocket protein-dependent cyclin A gene expression.
Received February 5, 2003; accepted May 13, 2003.
Address correspondence to: Dr. Richard K. Assoian, 167 Johnson Pavilion, 3620 Hamilton Walk, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084. Email: rka{at}pharm.med.upenn.edu
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