Horiuchi M, Hayashida W, Kambe T, Yamada T, Dzau V J
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
J Biol Chem. 1997 Jul 25;272(30):19022-6. doi: 10.1074/jbc.272.30.19022.
We examined the cellular and signaling mechanism of angiotensin II (Ang II) type 2 (AT2) receptor-induced apoptosis in PC12W (rat pheochromocytoma cell line) cells that express abundant AT2 receptor but not Ang II type 1 receptor. In these cells, nerve growth factor (NGF) inhibited the internucleosomal DNA fragmentation induced by serum depletion, whereas Ang II antagonized this NGF cell survival action and induced apoptosis. We studied the mechanism of NGF and AT2 receptor interaction on apoptosis by examining their effects on the survival factor Bcl-2. AT2 receptor activation did affect intracellular Bcl-2 protein levels. Bcl-2 phosphorylation was stimulated by NGF, whereas AT2 receptor activation blocked this NGF effect. Pretreatment with antisense oligonucleotide of mitogen-activated protein (MAP) kinase phosphatase-1 enhanced the effects of NGF on MAP kinase activation and Bcl-2 phosphorylation but attenuated the inhibitory effects of AT2 receptor on MAP kinase, Bcl-2 phosphorylation, and apoptosis. Taken together, these results suggest that MAP kinase plays a critical role in inhibiting apoptosis by phosphorylating Bcl-2. The AT2 receptor inhibits MAP kinase activation, resulting in the inactivation of Bcl-2 and the induction of apoptosis.
我们研究了血管紧张素II（Ang II）2型（AT2）受体在PC12W（大鼠嗜铬细胞瘤细胞系）细胞中诱导凋亡的细胞及信号传导机制，该细胞表达丰富的AT2受体但不表达血管紧张素II 1型受体。在这些细胞中，神经生长因子（NGF）抑制血清剥夺诱导的核小体间DNA片段化，而Ang II拮抗这种NGF的细胞存活作用并诱导凋亡。我们通过研究它们对存活因子Bcl-2的影响，探讨了NGF与AT2受体在凋亡方面相互作用的机制。AT2受体激活确实影响细胞内Bcl-2蛋白水平。NGF刺激Bcl-2磷酸化，而AT2受体激活则阻断这种NGF效应。用丝裂原活化蛋白（MAP）激酶磷酸酶-1的反义寡核苷酸预处理增强了NGF对MAP激酶激活和Bcl-2磷酸化的作用，但减弱了AT2受体对MAP激酶、Bcl-2磷酸化及凋亡的抑制作用。综上所述，这些结果表明MAP激酶通过使Bcl-2磷酸化在抑制凋亡中起关键作用。AT2受体抑制MAP激酶激活，导致Bcl-2失活并诱导凋亡。
