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Anti-apoptotic effect of SERM on the amyloid-β-induced apoptosis in PC12

SERM对淀粉样蛋白-β诱导的PC12细胞凋亡的抗凋亡作用

基本信息

批准号：
18591822
负责人：
TAKAHASHI Kazuhiro
金额：
$ 2.57万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591822/
关键词：
estroeen progesterone neurite outgrowth Rho Akt

项目摘要

Estrogen (E2) has direct in vivo and in vitro effects, such as inducing neurite outgrowth, on neurons. We investigated the morphological changes and intracellular signaling pathway induced by E2 in neuroblastoma (SH-SY5Y) cells. The effect of medroxyprogesterone acetate (MPA) or progesterone (P4) on the E2-induced neurite outgrowth was also examined using SH-SY5Y cells. Neurite outgrowth was induced by E2 in association with the phosphorylation of both Akt and extracellular signal-regulated kinase (ERK). These effects of E2, except for ERK phosphorylation, were abolished by MPA but not by P4. Progesterone receptor antagonist RU486 blocked the inhibitory effects of MPA. Estrogen receptor antagonist ICI 182, 780 and phosphatidylinositol 3-kinase inhibitor LY294002 inhibited the E2-induced neurite outgrowth. Because the Rho family of small GTPases has been shown to be involved in the regulation of neurite outgrowth, we examined the cross-talk among Rac1, Cdc42 and RhoA in the E2-induced neurite outgrowth. E2 immediately increased the Rac1 and Cdc42 activity and decreased the RhoA activity. E2-induced neurite outgrowth was attenuated in cells expressing dominant-negative mutants for Rac1 or Cdc42. These results suggest that regulation of Rho family GTPase activity by E2 is important for the neurite outgrowth in neuroblastoma cells, and that MPA, but not P4, may have an antagonistic effect against E2.

雌激素（E2）在体内和体外对神经元具有直接的作用，如诱导神经突起生长。本研究观察了E2诱导神经母细胞瘤细胞株SH-SY 5 Y的形态学变化及细胞内信号转导途径。用SH-SY 5 Y细胞观察醋酸甲羟孕酮（MPA）或孕酮（P4）对E2诱导的神经突起生长的影响。E2诱导神经突生长与Akt和细胞外信号调节激酶（ERK）的磷酸化有关。E2的这些作用，除了ERK磷酸化，被MPA取消，但不是由P4。孕酮受体拮抗剂RU 486可阻断MPA的抑制作用。雌激素受体拮抗剂ICI 182，780和磷脂酰肌醇3-激酶抑制剂LY 294002抑制E2诱导的神经突起生长。由于Rho家族的小GTP酶已被证明参与神经突生长的调节，我们研究了E2诱导的神经突生长中Rac 1，Cdc 42和RhoA之间的串扰。E2可使Rac 1和Cdc 42活性立即升高，而RhoA活性立即降低。在表达Rac 1或Cdc 42显性阴性突变体的细胞中，E2诱导的神经突生长被减弱。这些结果表明，调节Rho家族GT3活性的E2是重要的神经母细胞瘤细胞的神经突起生长，MPA，而不是P4，可能有拮抗作用，对E2。