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J. Biol. Chem., Vol. 278, Issue 17, 15421-15428, April 25, 2003

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Distinct Protein Kinase C Isoforms Mediate Regulation of Vascular Endothelial Growth Factor Expression by A_2A Adenosine Receptor Activation and Phorbol Esters in Pheochromocytoma PC12 Cells^*

Alicia M. Gardner and Mark E. Olah^§

From the Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0575

Vascular endothelial growth factor (VEGF) stimulates angiogenesis during development and in disease. In pheochromocytoma (PC12) cells, VEGF expression is regulated by A_2A adenosine receptor (A_2AAR) activation. The present work examines the underlying signaling pathway. The adenylyl cyclase-protein kinase A cascade has no role in the down-regulation of VEGF mRNA induced by the A_2AAR agonist, 2-[4-[(2-carboxyethyl)phenyl]ethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). Conversely, 6-h exposure of cells to either phorbol 12-myristate 13-acetate (PMA) or protein kinase C (PKC) inhibitors mimicked the CGS21680-induced down-regulation. PMA activated PKC, PKC, and PKC, and CGS21680 activated PKC and PKC as assessed by cellular translocation. By 6 h, PMA but not CGS21680 decreased PKC and PKC expression. Neither compound affected PKC levels. Following prolonged PMA treatment to down-regulate susceptible PKC isoforms, CGS21680 but not PMA inhibited the cobalt chloride induction of VEGF mRNA. The proteasome inhibitor, MG-132, abolished PMA- but not CGS21680-induced down-regulation of VEGF mRNA. Phorbol 12,13-diacetate reduced VEGF mRNA levels while down-regulating PKC but not PKC expression. In cells expressing a dominant negative PKC construct, CGS21680 was unable to reduce VEGF mRNA. Together, the findings suggest that phorbol ester-induced down-regulation of VEGF mRNA occurs as a result of a reduction of PKC activity, whereas that mediated by the A_2AAR occurs following deactivation of PKC.

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