Huang C, Schmid P C, Ma W Y, Schmid H H, Dong Z
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
J Biol Chem. 1997 Feb 14;272(7):4187-94. doi: 10.1074/jbc.272.7.4187.
Phorbol esters, which activate isoforms of protein kinase C, are general activators of the transcription factor activated protein 1 (AP-1). The pathway involved in this signal transduction is not very clear. Currently, little is known about whether phosphatidylinositol-3 (PI-3) kinase plays any role in phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced signal transduction. We demonstrate here that TPA not only has markedly synergistic effects on insulin-induced PI-3 kinase activity, but it also can induce PI-3 kinase activity and the PI-3 phosphates by itself. We also found that insulin, a PI-3 kinase activator, enhanced TPA-induced AP-1 trans-activation and transformation in JB6 promotion-sensitive cells. Furthermore, wortmannin and LY294002, two PI-3 kinase inhibitors, markedly decreased AP-1 activity induced by insulin, TPA, or TPA and insulin and inhibited JB6 promotion-sensitive cell transformation induced by TPA or TPA and insulin. Most importantly, constitutive overexpression of the dominant negative PI-3 kinase P85 mutants completely blocked insulin- or TPA-induced AP-1 trans-activation and TPA-induced cell transformation. All evidence from present studies suggests that PI-3 kinase acts as a mediator in TPA-induced AP-1 activation and transformation in JB6 cells.
佛波酯可激活蛋白激酶C的亚型，是转录因子激活蛋白1（AP-1）的通用激活剂。参与这种信号转导的途径尚不清楚。目前，关于磷脂酰肌醇-3（PI-3）激酶在佛波酯12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的信号转导中是否发挥作用知之甚少。我们在此证明，TPA不仅对胰岛素诱导的PI-3激酶活性有明显的协同作用，而且它自身也能诱导PI-3激酶活性和PI-3磷酸酯。我们还发现，PI-3激酶激活剂胰岛素增强了TPA诱导的AP-1反式激活以及在JB6促癌敏感细胞中的转化。此外，两种PI-3激酶抑制剂渥曼青霉素和LY294002显著降低了胰岛素、TPA或TPA与胰岛素共同诱导的AP-1活性，并抑制了TPA或TPA与胰岛素共同诱导的JB6促癌敏感细胞转化。最重要的是，显性负性PI-3激酶P85突变体的组成型过表达完全阻断了胰岛素或TPA诱导的AP-1反式激活以及TPA诱导的细胞转化。目前研究的所有证据表明，PI-3激酶在TPA诱导的JB6细胞中AP-1激活和转化过程中起介导作用。
