Wang D J, Huang N N, Heller E J, Heppel L A
Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853.
J Biol Chem. 1994 Jun 17;269(24):16648-55.
In Swiss 3T3 mouse fibroblasts, the mitogenic effect of extracellular ATP depends on stimulation of adenylyl cyclase. Lysophosphatidic acid (LPA) and phosphatidic acid (PA) inhibited adenylyl cyclase but synergized with ATP in mitogenic stimulation. This unusual synergism of two mitogens with opposite effects on cAMP levels was further investigated. LPA and PA inhibited the elevation of cAMP caused by cholera toxin, prostaglandin E2, or forskolin, but not the rise induced by ATP. In fact, ATP overcame the inhibitory effects of LPA or PA on cAMP levels. Indeed, in the presence of ATP and either cholera toxin or prostaglandin E2, LPA became a stimulator of adenylyl cyclase. Stimulation of DNA synthesis and inhibition of cAMP accumulation by LPA were inhibited by pertussis toxin, but with different dose-response characteristics. In addition, a normal mitogenic response to LPA was obtained in transfected mutant cells with a defective regulatory subunit for protein kinase A and in cells whose regulation of cAMP levels was abnormal because of overproduction of cAMP phosphodiesterase. The data support the hypothesis that the mitogenic effect of LPA involves a PTX-sensitive Gi protein but not inhibition of adenylyl cyclase.
在瑞士3T3小鼠成纤维细胞中，细胞外ATP的促有丝分裂作用取决于腺苷酸环化酶的激活。溶血磷脂酸（LPA）和磷脂酸（PA）抑制腺苷酸环化酶，但在促有丝分裂刺激中与ATP协同作用。对这种对cAMP水平具有相反作用的两种有丝分裂原的异常协同作用进行了进一步研究。LPA和PA抑制霍乱毒素、前列腺素E2或福斯高林引起的cAMP升高，但不抑制ATP诱导的升高。事实上，ATP克服了LPA或PA对cAMP水平的抑制作用。确实，在ATP与霍乱毒素或前列腺素E2同时存在的情况下，LPA成为腺苷酸环化酶的刺激物。百日咳毒素抑制LPA对DNA合成的刺激和对cAMP积累的抑制，但具有不同的剂量反应特征。此外，在蛋白激酶A调节亚基有缺陷的转染突变细胞以及由于cAMP磷酸二酯酶过量产生而导致cAMP水平调节异常的细胞中，获得了对LPA的正常促有丝分裂反应。这些数据支持这样的假设，即LPA的促有丝分裂作用涉及一种对百日咳毒素敏感的Gi蛋白，但不涉及对腺苷酸环化酶的抑制。
