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Nitric oxide (NO) regulates vascular smooth muscle cell (VSMC) structure and function, in part by activating soluble guanylate cyclase (sGC) to synthesize cGMP. The objective of this study was to further characterize the signaling mechanisms by which NO regulates VSMC gene expression using transcription profiling. DNA microarrays were hybridized with RNA extracted from rat pulmonary artery smooth muscle cells (RPaSMC) exposed to the NO donor compound, S-nitroso-glutathione (GSNO). Many of the genes, whose expression was induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER). sGC and cAMP-dependent protein kinase, but not cGMP-dependent protein kinase, were required for NO-mediated phosphorylation of CRE-binding protein (CREB) and induction of ICER gene expression. Expression of a dominant-negative CREB in RPaSMC prevented the NO-mediated induction of CRE-dependent gene transcription and ICER gene expression. Pre-treatment of RPaSMC with the intracellular calcium (Ca(2+)) chelator, BAPTA-AM, blocked the induction of ICER gene expression by GSNO. The store-operated Ca(2+) channel inhibitors, 2-ABP, and SKF-96365, reduced the GSNO-mediated increase in ICER mRNA levels, while 2-ABP did not inhibit GSNO-induced CREB phosphorylation. Our results suggest that induction of ICER gene expression by NO requires both CREB phosphorylation and Ca(2+) signaling. Transcription profiling of RPaSMC exposed to GSNO revealed important roles for sGC, PKA, CREB, and Ca(2+) in the regulation of gene expression by NO. The induction of ICER in GSNO-treated RPaSMC highlights a novel cross-talk mechanism between cGMP and cAMP signaling pathways.
Pubmed ID: 21642009
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CREB target gene database that uses a multi-layered approach to predict, validate and characterize CREB target genes. For each gene, the database tries to provide the following information: 1. CREB binding sites on the promoters 2. Promoter occupancy by CREB 3. Gene activation by cAMP in tissues CREB seems to occupy a large number of promoters in the genome (up to ~5000 in human), and the profiles for CREB promoter occupancy are very similar in different human tissues. However, only a small proportion of CREB occupied genes are induced by cAMP in any cell type, possibly reflecting the requirement of additional regulatory partners that assist in recruitment of the transcriptional apparatus. To use the database, choose the species, select the table you want to search, leave field (''All'') and type in the gene you want to search. A table listing the search results will be returned, followed by the description of the table. If no search result is returned, try the official gene symbol or gene ID (locuslink number) from NCBI Entrez Gene to search. Sponsors: This work was supported by National Institutes of Health Grants GM RO1-037828 (to M.M.) and DK068655 (to R.A.Y.).
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