Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 17, Pages 15421-15428Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M208366200
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Funding
- NCI NIH HHS [R01 CA79531] Funding Source: Medline
- NHLBI NIH HHS [5T32 HL07382] Funding Source: Medline
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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(2A)AR) 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(2)AAR agonist, 2-[4-[(2-carboxyethyl)phenyllethyl-amino]-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 PKCalpha, PKCepsilon, and PKCzeta, and CGS21680 activated PKCepsilon and PKCzeta as assessed by cellular translocation. By 6 h, PMA but not CGS21680 decreased PKCalpha and PKCepsilon expression. Neither compound affected PKCzeta 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 downregulation of VEGF mRNA. Phorbol 12,13-diacetate reduced VEGF mRNA levels while down-regulating PKCepsilon but not PKCalpha expression. In cells expressing a dominant negative PKCC 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 PKCepsilon activity, whereas that mediated by the A(2)AAR occurs following deactivation of PKC.
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