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)

Prostaglandin A2 (PGA2) potently inhibits cell proliferation and suppresses tumor growth in vivo, but little is known regarding the molecular mechanisms mediating these effects. Here we demonstrate that treatment of breast carcinoma MCF-7 cells with PGA2 leads to G1 arrest associated with a dramatic decrease in the levels of cyclin D1 and cyclin-dependent kinase 4 (cdk4) and accompanied by an increase in the expression of p21. We further show that these effects occur independent of cellular p53 status. The decline in cyclin D and cdk4 protein levels is correlated with loss in cdk4 kinase activity, cdk2 activity is also significantly inhibited in PGA2-treated cells, an effect closely associated with the upregulation of p21. Immunoprecipitation experiments verified that p21 was indeed complexed with cdk2 in PGA2-treated cells. Additional experiments with synchronized MCF-7 cultures stimulated with serum revealed that treatment with PGA2 prevents the progression of cells from G1 to S. Accordingly, the kinase activity associated with cdk4, cyclin E, and cdk2 immunocomplexes, which normally increases following serum addition, was unchanged in PGA2-treated cells. Furthermore, the retinoblastoma protein (Rb), a substrate of cdk4 and cdk2 whose phosphorylation is necessary for cell cycle progression, remains underphosphorylated in PGA2-treated serum-stimulated cells. These findings indicate that PGA2 exerts its growth-inhibitory effects through modulation of the expression and/or activity of several key G1 regulatory proteins. Our results highlight the chemotherapeutic potential of PGA2, particularly for suppressing growth of tumors lacking p53 function.
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PMID:Inhibition of G1 cyclin-dependent kinase activity during growth arrest of human breast carcinoma cells by prostaglandin A2. 862 77

Prostaglandin A2 (PGA2), a potent inhibitor of the growth of many cell types, inhibits G1 phase cyclin dependent kinases (cdk). Although PGA2 suppresses cyclin D1 and elevates p21Waf1 levels, it was the failure of cdk2 to become activated by phosphorylation which correlated best with growth inhibition. In kinetic studies, cdk2 activation was inhibited efficiently only if p21Waf1 levels increased prior to the activating phosphorylation; suggesting that p21Waf1 had blocked this phosphorylation. This model was confirmed in cells from p21Waf1 knockout mice where PGA2 was completely unable to block the activating phosphorylation of cdk2, or inhibit cdk2 activity. As expected, growth inhibition of p21Waf1(-/-) cells was not observed at PGA2 concentrations which inhibited cdk2 activity and growth of p21Waf1(+/+) cells.
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PMID:p21Waf1 inhibits the activity of cyclin dependent kinase 2 by preventing its activating phosphorylation. 974 75