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J Am Soc Nephrol 14:28-36, 2003
© 2003 American Society of Nephrology

Ca2+/Calmodulin-Dependent Protein Kinase II Stimulates c-fos Transcription and DNA Synthesis by a Src-Based Mechanism in Glomerular Mesangial Cells

Yuan Wang, Rangnath Mishra and Michael S. Simonson

Department of Medicine, Division of Nephrology, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio.

Correspondence to Dr. Michael S. Simonson, Department of Medicine, Division of Nephrology, Biomedical Research Building, Rm. 427, Case Western Reserve University, 2065 Adelbert Road, Cleveland, OH 44106. Phone: 216-368-1251; Fax: 216-368-1249;

ABSTRACT. 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 II{alpha}. 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. E-Mail: mss5@po.cwru.edu




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