Distinct protein kinase isoforms mediate regulation of vascular endothelial growth factor expression by A{2a} adenosine receptor activation and phorbol esters in pheochromocytoma PC12 cells

doi:10.1074/jbc.M208366200

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Papers In Press, published online ahead of print February 17, 2003
J. Biol. Chem, 10.1074/jbc.M208366200
Submitted on August 15, 2002
Revised on January 23, 2003
Accepted on February 17, 2003

Distinct protein kinase 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

Pharmacology, University of Cincinnati, Cincinnati, OH 45267-0575

Corresponding Author: mark.olah{at}UC.edu

Vascular endothelial growth factor (VEGF) stimulates angiogenesis during development and 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 downregulation of VEGF mRNA induced by the A_2AAR agonist, 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 downregulation. PMA activated PKC $alpha$ , PKC $epsilon$ and PKC $zeta$ and CGS21680 activated PKC $epsilon$ and PKC $zeta$ as assessed by cellular translocation. By 6 h, PMA but not CGS21680 decreased PKC $alpha$ and PKC $epsilon$ expression. Neither compound affected PKC $zeta$ levels. Following prolonged PMA treatment to downregulate 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 downregulation of VEGF mRNA. Phorbol 12,13-diacetate reduced VEGF mRNA levels while downregulating PKC $epsilon$ but not PKC $alpha$ expression. In cells expressing a dominant negative PKC $zeta$ construct, CGS21680 was unable to reduce VEGF mRNA. Together, the findings suggest that phorbol ester-induced downregulation of VEGF mRNA occurs due to a reduction of PKC $epsilon$ activity while that mediated by the A_2AAR occurs following deactivation of PKC $zeta$ .

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