MUTANT P53 POTENTIATES PROTEIN-KINASE-C INDUCTION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION

Many tumor cells produce vascular endothelial growth factor (VEGF), wh ich is thought to be a pivotal mediator of tumor neoangiogenesis. Expr ession of the VEGF gene can be induced by tumor promoting phorbol este rs, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), which activate protein kinase C (PKC). Here we show that in transient transfection a ssays a mutated form of the murine p53 tumor suppressor gene (ala135-- >val) induces expression of VEGF mRNA and potentiates TPA stimulated V EGF mRNA expression. In NM 3T3 cells which stably overexpress the temp erature sensitive p53 (ala135-->val), displaying mutant phenotype at 3 7 degrees C and wildtype phenotype at 32.5 degrees C, induction of VEG F mRNA and protein by activated PKC is strongly synergistic with mutan t, but not wildtype p53. Mutant p53 specifically increases TPA inducti on of VEGF without affecting the expression of other TPA inducible gen es. TPA dependent VEGF expression is also enhanced by human p53 mutate d at amino acid 175. Thus, our data link PKC and p53, the gene most fr equently altered in human tumors, with the regulation of tumor angioge nesis.