cGMP-independent nitric oxide signaling and regulation of the cell cycle
<p>Abstract</p> <p>Background</p> <p>Regulatory functions of nitric oxide (NO<sup>•</sup>) that bypass the second messenger cGMP are incompletely understood. Here, cGMP-independent effects of NO<sup>• </sup>on gene expression were globally examin...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2005-11-01
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| Series: | BMC Genomics |
| Online Access: | http://www.biomedcentral.com/1471-2164/6/151 |
| _version_ | 1818229412448960512 |
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| author | Cintron Ana Munson Peter J Barb Jennifer J Sittler Kelly J Goldberg Ilana G Myers Daniela E Ma Penglin Zhang Jianhua Cui Xiaolin McCoy J Philip Wang Shuibang Danner Robert L |
| author_facet | Cintron Ana Munson Peter J Barb Jennifer J Sittler Kelly J Goldberg Ilana G Myers Daniela E Ma Penglin Zhang Jianhua Cui Xiaolin McCoy J Philip Wang Shuibang Danner Robert L |
| author_sort | Cintron Ana |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Regulatory functions of nitric oxide (NO<sup>•</sup>) that bypass the second messenger cGMP are incompletely understood. Here, cGMP-independent effects of NO<sup>• </sup>on gene expression were globally examined in U937 cells, a human monoblastoid line that constitutively lacks soluble guanylate cyclase. Differentiated U937 cells (>80% in G0/G1) were exposed to S-nitrosoglutathione, a NO<sup>• </sup>donor, or glutathione alone (control) for 6 h without or with dibutyryl-cAMP (Bt<sub>2</sub>cAMP), and then harvested to extract total RNA for microarray analysis. Bt<sub>2</sub>cAMP was used to block signaling attributable to NO<sup>•</sup>-induced decreases in cAMP.</p> <p>Results</p> <p>NO<sup>• </sup>regulated 110 transcripts that annotated disproportionately to the cell cycle and cell proliferation (47/110, 43%) and more frequently than expected contained AU-rich, post-transcriptional regulatory elements (ARE). Bt<sub>2</sub>cAMP regulated 106 genes; cell cycle gene enrichment did not reach significance. Like NO<sup>•</sup>, Bt<sub>2</sub>cAMP was associated with ARE-containing transcripts. A comparison of NO<sup>• </sup>and Bt<sub>2</sub>cAMP effects showed that NO<sup>• </sup>regulation of cell cycle genes was independent of its ability to interfere with cAMP signaling. Cell cycle genes induced by NO<sup>• </sup>annotated to G1/S (7/8) and included E2F1 and p21/Waf1/Cip1; 6 of these 7 were E2F target genes involved in G1/S transition. Repressed genes were G2/M associated (24/27); 8 of 27 were known targets of p21. E2F1 mRNA and protein were increased by NO<sup>•</sup>, as was E2F1 binding to E2F promoter elements. NO<sup>• </sup>activated p38 MAPK, stabilizing p21 mRNA (an ARE-containing transcript) and increasing p21 protein; this increased protein binding to CDE/CHR promoter sites of p21 target genes, repressing key G2/M phase genes, and increasing the proportion of cells in G2/M.</p> <p>Conclusion</p> <p>NO<sup>• </sup>coordinates a highly integrated program of cell cycle arrest that regulates a large number of genes, but does not require signaling through cGMP. In humans, antiproliferative effects of NO<sup>• </sup>may rely substantially on cGMP-independent mechanisms. Stress kinase signaling and alterations in mRNA stability appear to be major pathways by which NO<sup>• </sup>regulates the transcriptome.</p> |
| first_indexed | 2024-12-12T10:18:11Z |
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| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-12T10:18:11Z |
| publishDate | 2005-11-01 |
| publisher | BMC |
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| series | BMC Genomics |
| spelling | doaj.art-d0dbf089753645f38ac383cff822facc2022-12-22T00:27:37ZengBMCBMC Genomics1471-21642005-11-016115110.1186/1471-2164-6-151cGMP-independent nitric oxide signaling and regulation of the cell cycleCintron AnaMunson Peter JBarb Jennifer JSittler Kelly JGoldberg Ilana GMyers Daniela EMa PenglinZhang JianhuaCui XiaolinMcCoy J PhilipWang ShuibangDanner Robert L<p>Abstract</p> <p>Background</p> <p>Regulatory functions of nitric oxide (NO<sup>•</sup>) that bypass the second messenger cGMP are incompletely understood. Here, cGMP-independent effects of NO<sup>• </sup>on gene expression were globally examined in U937 cells, a human monoblastoid line that constitutively lacks soluble guanylate cyclase. Differentiated U937 cells (>80% in G0/G1) were exposed to S-nitrosoglutathione, a NO<sup>• </sup>donor, or glutathione alone (control) for 6 h without or with dibutyryl-cAMP (Bt<sub>2</sub>cAMP), and then harvested to extract total RNA for microarray analysis. Bt<sub>2</sub>cAMP was used to block signaling attributable to NO<sup>•</sup>-induced decreases in cAMP.</p> <p>Results</p> <p>NO<sup>• </sup>regulated 110 transcripts that annotated disproportionately to the cell cycle and cell proliferation (47/110, 43%) and more frequently than expected contained AU-rich, post-transcriptional regulatory elements (ARE). Bt<sub>2</sub>cAMP regulated 106 genes; cell cycle gene enrichment did not reach significance. Like NO<sup>•</sup>, Bt<sub>2</sub>cAMP was associated with ARE-containing transcripts. A comparison of NO<sup>• </sup>and Bt<sub>2</sub>cAMP effects showed that NO<sup>• </sup>regulation of cell cycle genes was independent of its ability to interfere with cAMP signaling. Cell cycle genes induced by NO<sup>• </sup>annotated to G1/S (7/8) and included E2F1 and p21/Waf1/Cip1; 6 of these 7 were E2F target genes involved in G1/S transition. Repressed genes were G2/M associated (24/27); 8 of 27 were known targets of p21. E2F1 mRNA and protein were increased by NO<sup>•</sup>, as was E2F1 binding to E2F promoter elements. NO<sup>• </sup>activated p38 MAPK, stabilizing p21 mRNA (an ARE-containing transcript) and increasing p21 protein; this increased protein binding to CDE/CHR promoter sites of p21 target genes, repressing key G2/M phase genes, and increasing the proportion of cells in G2/M.</p> <p>Conclusion</p> <p>NO<sup>• </sup>coordinates a highly integrated program of cell cycle arrest that regulates a large number of genes, but does not require signaling through cGMP. In humans, antiproliferative effects of NO<sup>• </sup>may rely substantially on cGMP-independent mechanisms. Stress kinase signaling and alterations in mRNA stability appear to be major pathways by which NO<sup>• </sup>regulates the transcriptome.</p>http://www.biomedcentral.com/1471-2164/6/151 |
| spellingShingle | Cintron Ana Munson Peter J Barb Jennifer J Sittler Kelly J Goldberg Ilana G Myers Daniela E Ma Penglin Zhang Jianhua Cui Xiaolin McCoy J Philip Wang Shuibang Danner Robert L cGMP-independent nitric oxide signaling and regulation of the cell cycle BMC Genomics |
| title | cGMP-independent nitric oxide signaling and regulation of the cell cycle |
| title_full | cGMP-independent nitric oxide signaling and regulation of the cell cycle |
| title_fullStr | cGMP-independent nitric oxide signaling and regulation of the cell cycle |
| title_full_unstemmed | cGMP-independent nitric oxide signaling and regulation of the cell cycle |
| title_short | cGMP-independent nitric oxide signaling and regulation of the cell cycle |
| title_sort | cgmp independent nitric oxide signaling and regulation of the cell cycle |
| url | http://www.biomedcentral.com/1471-2164/6/151 |
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