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)

Using microarray analysis, we have detected downregulation of several components of the cGMP signaling pathway during replicative senescence of primary human diploid fibroblasts (HDFs). Therefore, the effect of pharmacological inhibition of cGMP synthesis was analyzed in HDFs. Treatment with 6-anilino-5,8-quinolinequinone (LY83583, referred to as LY hereafter), a previously described inhibitor of guanylate cyclase, induced cellular senescence. Microarray analysis revealed that LY treatment induced the Cdk inhibitor p21(WAF1/SDI/CIP1). In colorectal cancer cells, transcription of p21 was induced by LY in a p53-independent manner. Furthermore, p21, but not p53, was required for inhibition of proliferation by LY. The lack of p53 involvement suggests that LY does not induce DNA damage. Growth inhibition was also observed in malignant melanoma and breast cancer cell lines. Functional inactivation of the retinoblastoma tumor-suppressor protein, an effector of p21-mediated cell-cycle inhibition, converted LY-induced growth arrest to apoptosis. These results suggest that LY, or derivatives, may be useful therapeutic agents for the treatment of tumors.
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PMID:Induction of the Cdk inhibitor p21 by LY83583 inhibits tumor cell proliferation in a p53-independent manner. 1246 77

Vascular smooth muscle (VSM) growth is integral in the pathophysiology of blood vessel diseases, and identifying approaches that have capacity to regulate VSM growth is critically essential. Cyclic nucleotide signaling has been generally considered protective in cardiac and vascular tissues and has been the target of numerous basic science and clinical studies. In this project, the influence of BAY 41-2272 (BAY), a recently described soluble guanylate cyclase stimulator and inducer of cyclic guanosine monophosphate (cGMP) synthesis, on VSM cell growth was analyzed. In rat A7R5 VSM cells, BAY significantly reduced proliferation in a dose- and time-dependent fashion. BAY activated cGMP and cyclic adenosine monophosphate (cAMP) signaling evidenced through elevated cGMP and cAMP content, increased expression of cyclic nucleotide-dependent protein kinases, and differential vasodilator-stimulated phosphoprotein phosphorylation. BAY significantly elevated cyclin E expression, decreased expression of the regulatory cyclin-dependent kinases -2 and -6, increased expression of cell cycle inhibitory p21 WAF1/Cip1 and p27 Kip1, and reduced expression of phosphorylated focal adhesion kinase. These comprehensive findings provide first evidence for the antigrowth cell cycle-regulatory properties of the neoteric agent, BAY 41-2272, in VSM and lend support for its continued study in the clinical and basic cardiovascular sciences.
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PMID:Antigrowth properties of BAY 41-2272 in vascular smooth muscle cells. 1918 37