p90 Ribosomal S6 kinases play a significant role in early gene regulation in the cardiomyocyte response to Gq-protein-coupled receptor stimuli, endothelin-1 and α1-adrenergic receptor agonists
| Autor: | Emre Amirak, Stephen J. Fuller, Peter H. Sugden, Angela Clerk |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
α1-adrenergic receptor GSK3α/β glycogen synthase kinase 3α/β cardiomyocyte Olr1 oxidized low-density lipoprotein (lectin-like) receptor 1 Biochemistry Rats Sprague-Dawley transcriptomics CREB cAMP-response-element-binding protein Plk2 polo-like kinase 2 AR adrenergic receptor Klf Krüppel-like factor Ptgs2 prostaglandin-endoperoxide synthase 2 qPCR quantitative PCR Gene expression SNK Student–Newman–Keuls p90 ribosomal S6 kinase (p90 RSK) Egr early growth response MSK mitogen- and stress-activated protein kinase Myocytes Cardiac Receptor ERK1/2 extracellular-signal-regulated kinase 1/2 Regulation of gene expression Areg amphiregulin Mitogen-Activated Protein Kinase 3 biology Kinase Receptor Endothelin A RSK ribosomal S6 kinase Gq alpha subunit Benzamides Signal transduction endothelin Adrenergic alpha-Agonists NPE nuclear protein-enriched Research Article Signal Transduction Agonist PKB protein kinase B FDR false discovery rate medicine.drug_class Dusp dual-specificity phosphatase IL11 interleukin 11 MKK MAPK kinase Gapdh glyceraldehyde 3-phosphate dehydrogenase Ribosomal Protein S6 Kinases 90-kDa Lif leukaemia inhibitory factor Receptors Adrenergic alpha-1 medicine ET-1 endothelin-1 Animals mitogen-activated protein kinase (MAPK) Fosb FBJ murine osteosarcoma viral oncogene homologue B Molecular Biology Transcription factor BH-MTC Benjamini and Hochberg multiple testing correction Cell Nucleus Nr4a nuclear receptor subfamily 4 group A PE phenylephrine Cell Biology Molecular biology Rgs2 regulator of G-protein signalling 2 24 kDa Rats Has hyaluronan synthase Atf3 activating transcription factor 3 Gene Expression Regulation MNK MAPK-interacting protein kinase biology.protein AMPKα AMP-activated protein kinase α RNA Sik1 salt-inducible kinase 1 MAPK mitogen-activated protein kinase |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | ERK1/2 (extracellular-signal-regulated kinase 1/2) and their substrates RSKs (p90 ribosomal S6 kinases) phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. In the present study we investigated the role of RSKs in the transcriptomic responses to the Gq-protein-coupled receptor agonists endothelin-1, phenylephrine (a generic α1-adrenergic receptor agonist) and A61603 (α1A-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2–3 min of stimulation (endothelin-1>A61603≈phenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased the nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of the 213 RNAs up-regulated after 1 h, 51% required RSKs for their up-regulation, whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical with, endothelin-1. As with endothelin-1, PD184352 inhibited the up-regulation of most phenylephrine-responsive transcripts, but the greater variation in the effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α1A-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, up-regulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to Gq-protein-coupled receptor stimulation. |
| Databáze: | OpenAIRE |
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