Monaco L, Conti M
Mol Cell Endocrinol. 1987 Feb;49(2-3):227-36. doi: 10.1016/0303-7207(87)90217-6.
Several tumor promoters exert their effects by activating a Ca2+-phospholipid-dependent protein kinase (protein kinase C). To study the role of this protein kinase in the regulation of Sertoli cell function, we have evaluated the effect of phorbol esters, mezerein, and teleocidin on the response of the Sertoli cell to FSH. Cells were treated for different time intervals with the tumor promoters, and cell response was measured by stimulating the cell with FSH. 12-O-Tetradecanoylphorbol 13-acetate (TPA) had no significant effect on basal cAMP production but markedly inhibited the cAMP response to FSH. Significant inhibition of cAMP accumulation was observed after 15 min treatment with 100 nM TPA, and maximal inhibition developed within 1 h. The decrease in cAMP accumulation was dependent on the dose of phorbol ester used, with an estimated ED50 of 10-20 nM TPA. In a manner similar to TPA, mezerein and teleocidin also inhibited the cAMP response of the Sertoli cell, while the phorbol ester 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), inactive as a tumor promoter and unable to stimulate protein kinase C activity, was devoid of effect. The promoters that inhibited cAMP response also inhibited the FSH-stimulated androgen aromatization. The dose of TPA producing half-maximal inhibition of estrogen accumulation was again 10-20 nM TPA, mezerein, and teleocidin inhibited estrogen accumulation whether FSH, forskolin or cholera toxin was used to stimulate the Sertoli cell. In contrast, only FSH-dependent cAMP accumulation was inhibited by the tumor promoters, while forskolin and cholera toxin stimulations were not affected. These data suggest that tumor promoters which activate protein kinase C act at two sites of the Sertoli cell response. They alter receptor-mediated signal transduction across the membrane and affect steroidogenesis at a site distal to cAMP accumulation.
几种肿瘤启动子通过激活一种钙-磷脂依赖性蛋白激酶（蛋白激酶C）发挥其作用。为了研究这种蛋白激酶在支持细胞功能调节中的作用，我们评估了佛波酯、大戟二萜醇酯和杀鱼菌素对支持细胞对促卵泡激素（FSH）反应的影响。用肿瘤启动子处理细胞不同时间间隔，然后用FSH刺激细胞来测量细胞反应。12-O-十四烷酰佛波醇-13-乙酸酯（TPA）对基础环磷酸腺苷（cAMP）生成没有显著影响，但显著抑制了对FSH的cAMP反应。用100 nM TPA处理15分钟后观察到cAMP积累有显著抑制，1小时内达到最大抑制。cAMP积累的减少取决于所用佛波酯的剂量，估计TPA的半数有效剂量（ED50）为10 - 20 nM。与TPA类似，大戟二萜醇酯和杀鱼菌素也抑制支持细胞的cAMP反应，而作为肿瘤启动子无活性且不能刺激蛋白激酶C活性的佛波酯4α-佛波醇12,13-二癸酸酯（4α-PDD）则没有作用。抑制cAMP反应的启动子也抑制了FSH刺激的雄激素芳香化。产生雌激素积累半数最大抑制的TPA剂量再次为10 - 20 nM TPA，无论使用FSH、福斯高林还是霍乱毒素刺激支持细胞，大戟二萜醇酯和杀鱼菌素都抑制雌激素积累。相反，肿瘤启动子仅抑制FSH依赖性的cAMP积累，而福斯高林和霍乱毒素刺激不受影响。这些数据表明，激活蛋白激酶C的肿瘤启动子在支持细胞反应的两个位点起作用。它们改变受体介导的跨膜信号转导，并在cAMP积累远端的位点影响类固醇生成。
