Prostacylin receptor activation inhibits proliferation of aortic smooth muscle cells by regulating cAMP response element-binding protein- and pocket protein-dependent cyclin a gene expression.
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.
Kothapalli
Devashish
D
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, USA.
Stewart
Sheryl A
SA
Smyth
Emer M
EM
Azonobi
Ijeoma
I
Pure
Ellen
E
Assoian
Richard K
RK
D001011:Aorta / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019925:Cyclin A / Q000096:biosynthesis* / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016196:S Phase / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D019927:Cyclin E; D011464:Epoprostenol; C043867:cicaprost