Ca2+/calmodulin-dependent protein kinase II stimulates c-fos transcription and DNA synthesis by a Src-based mechanism in glomerular mesangial cells.
Mesangial cell growth factors elevate intracellular free [Ca2+]i, but mechanisms linking [Ca2+]i to gene expression and DNA synthesis are unclear. This study investigated the hypothesis that Ca2+/calmodulin-dependent protein kinase II (CaMK II), which is activated by elevated [Ca2+]i, increases c-fos transcription and DNA synthesis via a Src-based mechanism. In cultured rat mesangial cells, dominant negative Src (SrcK-) blocked activation of the c-fos gene promoter by CaMK II 290, a constitutively active form of CaMK IIalpha. Activation of the c-fos promoter by CaMK II 290 was also blocked by COOH-terminal Src kinase, which phosphorylates and inactivates c-Src. A pharmacologic CaMK inhibitor, KN-93, did not block activation of the c-fos promoter by ectopically expressed v-Src. Stimulation of c-Src by endothelin-1 required CaMK II activity, further supporting the notion that CaMK II acts upstream of Src in a signaling cassette. Activation of the c-fos promoter by CaMKII290 and Src required the c-fos serum response element. Dominant negative SrcK- also blocked induction of DNA synthesis in mesangial cells by CaMK II 290. Collectively, these results suggest that in mesangial cells Src protein tyrosine kinases act downstream of CaMKII in a signaling pathway in which [Ca2+]i induces the c-fos promoter and increases DNA synthesis.
Wang
Yuan
Y
Department of Medicine, Division of Nephrology, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Mishra
Rangnath
R
Simonson
Michael S
MS
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000494:pharmacology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005799:Genes, Dominant; D016762:Genes, fos / Q000187:drug effects*; D016391:Genes, src / Q000502:physiology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D027602:Serum Response Element / Q000502:physiology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D019061:src-Family Kinases / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004247:DNA; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D019061:src-Family Kinases; C072105:KN 93; D000096926:Benzenesulfonamides