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首页> 外文期刊>Molecular and Cellular Biology >Antagonistic Effects of Protein Kinase C α and δ on Both Transformation and Phospholipase D Activity Mediated by the Epidermal Growth Factor Receptor
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Antagonistic Effects of Protein Kinase C α and δ on Both Transformation and Phospholipase D Activity Mediated by the Epidermal Growth Factor Receptor

机译：蛋白激酶Cα和δ对表皮生长因子受体介导的转化和磷脂酶D活性的拮抗作用

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Downregulation of protein kinase C δ (PKC δ) by treatment with the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) transforms cells that overexpress the non-receptor class tyrosine kinase c-Src (Z. Lu et al., Mol. Cell. Biol. 17:3418–3428, 1997). We extended these studies to cells overexpressing a receptor class tyrosine kinase, the epidermal growth factor (EGF) receptor (EGFR cells); like c-Src, the EGF receptor is overexpressed in several human tumors. In contrast with expectations, downregulation of PKC isoforms with TPA did not transform the EGFR cells; however, treatment with EGF did transform these cells. Since TPA downregulates all phorbol ester-responsive PKC isoforms, we examined the effects of PKC δ- and PKC α-specific inhibitors and the expression of dominant negative mutants for both PKC δ and α. Consistent with a tumor-suppressing function for PKC δ, the PKC δ-specific inhibitor rottlerin and a dominant negative PKC δ mutant transformed the EGFR cells in the absence of EGF. In contrast, the PKC α-specific inhibitor Go6976 and expression of a dominant negative PKC α mutant blocked the transformed phenotype induced by both EGF and PKC δ inhibition. Interestingly, both rottlerin and EGF induced substantial increases in phospholipase D (PLD) activity, which is commonly elevated in response to mitogenic stimuli. The elevation of PLD activity in response to inhibiting PKC δ, like transformation, was dependent upon PKC α and restricted to the EGFR cells. These data demonstrate that PKC isoforms α and δ have antagonistic effects on both transformation and PLD activity and further support a tumor suppressor role for PKC δ that may be mediated by suppression of tyrosine kinase-dependent increases in PLD activity.
机译：通过用促肿瘤的佛波酯12- O -十四烷酰佛波醇13-乙酸酯（TPA）处理，蛋白激酶Cδ（PKCδ）的下调转化了过度表达非受体类酪氨酸激酶c的细胞-Src（Z. Lu et al。，Mol。Cell。Biol。17：3418-3428，1997）。我们将这些研究扩展到过表达受体类酪氨酸激酶，表皮生长因子（EGF）受体（EGFR细胞）的细胞。像c-Src一样，EGF受体在几种人类肿瘤中过表达。与预期相反，TPA对PKC亚型的下调不能转化EGFR细胞。然而，用EGF处理确实能转化这些细胞。由于TPA下调了所有对佛波酯反应性的PKC同工型，因此我们检查了PKCδ和PKCα特异性抑制剂的作用以及PKCδ和α的显性负突变体的表达。与PKCδ的肿瘤抑制功能一致，PKCδ特异性抑制剂rottlerin和显性负PKCδ突变体在没有EGF的情况下转化了EGFR细胞。相反，PKCα特异性抑制剂Go6976和显性负PKCα突变体的表达阻断了EGF和PKCδ抑制作用诱导的转化表型。有趣的是，rottlerin和EGF均可诱导磷脂酶D（PLD）活性的显着增加，而这通常在对促有丝分裂刺激的响应中会升高。像转化一样，对抑制PKCδ的响应，PLD活性的升高取决于PKCα，并且仅限于EGFR细胞。这些数据证明PKC同工型α和δ对转化和PLD活性均具有拮抗作用，并且进一步支持PKCδ的肿瘤抑制作用，其可能通过抑制酪氨酸激酶依赖性PLD活性的增加而介导。

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