c-Jun kinase mediates expression of VEGF induced at transcriptional level by Rac1 and Cdc42Hs but not by RhoA.
Tumour angiogenesis is mediated by increased levels of vascular endothelial growth factor (VEGF). We have studied the mechanism by which endogenous activation of Rho oncoproteins regulates VEGF expression in COS-7 and NIH3T3 cells. We carried out transient and stable transfection with constitutively activated rhoA, rac1, and cdc42 mutants in COS-7 and NIH3T3 cells, respectively in the absence of external stimuli. Western blot and inmunohistochemistry assays of those cells revealed increased VEGF protein expression. Cotransfection with constitutively activated rhoA, rac1, and cdc42 mutants and a VEGF promoter-reporter construct showed an increase in VEGF promoter transcriptional activity induced by Rho oncoproteins in COS-7 and NIH3T3. c-Jun kinase had been described as a MAPK involved in Rho oncoproteins pathways. Interestingly, we found that c-Jun kinase chemical inhibition as well as transient transactivation assays using dominant negative c-Jun kinase mutant abolished the VEGF promoter transcriptional induction by Rac1 and Cdc42 but not by RhoA. These findings indicate that Rho oncoprotein endogenously activated regulates VEGF expression through a transcriptional mechanism, and that the c-Jun kinase activity is a mediator in the expression of VEGF induced by Rac1 and Cdc42 oncoproteins, but not of that induced by RhoA.
Saníger
M Luisa
ML
Departamento de Biología Experimental, Universidad de Jaén, Campus de las Lagunillas s/n, 23071 Jaén, Spain.
Oya
Ricardo
R
Macías
David
D
Domínguez
Jorge N
JN
Aránega
Amelia
A
Luque
Francisco
F
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D048031:JNK Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein