Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression.
Many tumor cells produce vascular endothelial growth factor (VEGF), which is thought to be a pivotal mediator of tumor neoangiogenesis. Expression of the VEGF gene can be induced by tumor promoting phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), which activate protein kinase C (PKC). Here we show that in transient transfection assays a mutated form of the murine p53 tumor suppressor gene (ala135-->val) induces expression of VEGF mRNA and potentiates TPA stimulated VEGF mRNA expression. In NIH 3T3 cells which stably overexpress the temperature sensitive p53 (ala135-->val), displaying mutant phenotype at 37 degrees C and wildtype phenotype at 32.5 degrees C, induction of VEGF mRNA and protein by activated PKC is strongly synergistic with mutant, but not wildtype p53. Mutant p53 specifically increases TPA induction of VEGF without affecting the expression of other TPA inducible genes. TPA dependent VEGF expression is also enhanced by human p53 mutated at amino acid 175. Thus, our data link PKC and p53, the gene most frequently altered in human tumors, with the regulation of tumor angiogenesis.
Kieser
A
A
Institut für Molekulare Zellbiologie, Universität Freiburg, Germany.
Weich
H A
HA
Brandner
G
G
Marmé
D
D
Kolch
W
W
D016475:3T3 Cells; D000818:Animals; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation; D016158:Genes, p53; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009154:Mutation; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate