Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was performed to investigate whether the expression of p21(Sdi1/Cip1/Waf1), one of the cyclin-dependent kinase inhibitor proteins, could be regulated by nitric oxide (NO) and might account for the antiproliferative effect of NO. Quiescent adventitial fibroblasts were stimulated to proliferate by serum addition and by NO donors added during different phases of the cell cycle. [(3)H]Thymidine incorporation was markedly reduced by S-nitroso-N-acetyl-penicillamine (SNAP) added either with serum at quiescence or at later time point in the cell cycle. Northern and Western blot analyses showed that addition of SNAP either at quiescence or 15 hours after serum addition induced a rapid induction of p21 mRNA and protein. Immunoprecipitation studies and electrophoretic mobility shift analysis indicate that the treatment of cells with SNAP induced the phosphorylation of p53 (a tumor suppressor protein) and enhanced the ability of p53 to bind DNA when SNAP was added during the cell cycle. The increased expression of p21 mRNA or p53 activation during late G(1) or S phase was also caused by addition of 8-bromo-cGMP and effectively blocked by a specific inhibitor of the soluble guanylate cyclase. Furthermore, this response to SNAP was blocked by an inhibitor of protein kinase G. These studies implicate NO as a potential regulator of the cell cycle in aortic adventitial fibroblasts through a cGMP-mediated transcriptional mechanism involving the induction of p21.
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PMID:Nitric oxide-induced increase in p21(Sdi1/Cip1/Waf1) expression during the cell cycle in aortic adventitial fibroblasts. 1063 97

During vascular injury, the proliferation and migration of smooth muscle cells leads to characteristic neointima formation, which can be exacerbated by genetic depletion of caveolin-1 or heme oxygenase 1 (HO-1), and inhibited by carbon monoxide (CO), a by-product of heme oxygenase 1 activity. CO inhibited smooth muscle cell proliferation by activating p38 mitogen-activated protein kinase (MAPK) and p21(Waf1/Cip1). Exposure to CO increased caveolin-1 expression in neointimal lesions of injured aorta and in vitro by activating guanylyl cyclase and p38 MAPK. p38beta-/- fibroblasts did not induce caveolin-1 in response to CO, and exhibited a diminished basal caveolin-1 expression, which was restored by p38beta gene transfer. p38beta MAPK down-regulated extracellular signal-regulated protein kinase 1/2 (ERK-1/2), which can repress caveolin-1 transcription. Genetic depletion of caveolin-1 abolished the antiproliferative effect of CO. Thus, we demonstrate that CO, by activating p38beta MAPK, up-regulates caveolin-1, which acts as a tumor suppressor protein that mediates the growth inhibitory properties of this gas.
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PMID:Caveolin-1 expression by means of p38beta mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide. 1605 4