Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID: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. 1286 29

Prostacyclin has many effects in the vasculature; one of the less well understood is the ability to block cell cycle progression through G(1) phase. We previously reported that the prostacyclin mimetic, cicaprost, selectively inhibits cyclin E-cyclin-dependent kinase-2 (Cdk2), and now we show that it acts by regulating the expression of Skp2, the F-box protein that targets p27(Kip1) for ubiquitin-mediated proteolysis. First, we show that cicaprost prevents the late G(1) phase down-regulation of p27(Kip1) and that the inhibitory effect of cicaprost on cyclin E-Cdk2 activity and S phase entry is eliminated by deleting p27(Kip1). Levels of the closely related Cdk2 inhibitor, p21(Cip1), are unaffected by cicaprost. Moreover, we show that cicaprost blocks the induction of Skp2 mRNA and that ectopic expression of a Skp2 cDNA overrides the effect of cicaprost on p27(Kip1) levels and S phase entry. Our data show that inhibition of F-box protein gene expression can underlie the effect of a potent antimitogen.
 ...
PMID:Antimitogenesis linked to regulation of Skp2 gene expression. 1512 98

The prostanoid prostacyclin (PGI2) inhibits proliferation of cultured vascular SMCs by inhibiting cell cycle progression from G1 to S phase. Progression through G1 phase is regulated by the sequential activation of the G1 phase cyclin-dependent kinases (cdks). Recent studies have shown that PGI2-dependent activation of its receptor, IP, inhibits G1 phase progression by blocking the degradation of p27 and the activation of cyclin E-cdk2. High Density Lipoproteins (HDL) and its associated apolipoprotein, ApoE, also inhibit S phase entry of vascular SMCs, and the effects of HDL and ApoE are, at least in part, also mediated by the production of PGI2. The antimitogenic effects of hyaluronan may also be controlled by PGI2. This review summarizes the effects of PGI2 on the G1 phase cyclin-cdks and discusses the potential role of PGI2 as a common component of multiple extracellular signals that attenuate the proliferation of vascular SMCs.
 ...
PMID:Antimitogenic effects of prostacyclin on the G1 phase cyclin-dependent kinases. 1630 99