Kieser A, Weich H A, Brandner G, Marmé D, Kolch W
Institut für Molekulare Zellbiologie, Universität Freiburg, Germany.
Oncogene. 1994 Mar;9(3):963-9.
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.
许多肿瘤细胞会产生血管内皮生长因子（VEGF），它被认为是肿瘤新生血管形成的关键介质。VEGF基因的表达可被促肿瘤佛波酯诱导，如12 - O - 十四酰佛波醇 - 13 - 乙酸酯（TPA），其可激活蛋白激酶C（PKC）。在此我们表明，在瞬时转染实验中，鼠源p53肿瘤抑制基因的一种突变形式（ala135→val）可诱导VEGF mRNA的表达，并增强TPA刺激的VEGF mRNA表达。在稳定过表达温度敏感型p53（ala135→val）的NIH 3T3细胞中，该细胞在37℃时表现出突变表型，在32.5℃时表现出野生型表型，活化的PKC对VEGF mRNA和蛋白的诱导与突变型p53具有强烈协同作用，而与野生型p53则无协同作用。突变型p53可特异性增加TPA对VEGF的诱导作用，而不影响其他TPA诱导基因的表达。在氨基酸175处发生突变的人p53也可增强TPA依赖性VEGF的表达。因此，我们的数据将PKC和p53（人类肿瘤中最常发生改变的基因）与肿瘤血管生成的调控联系了起来。
