17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts
17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts
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17b-雌二醇通过促进成骨细胞中 TFII-I 依赖性 Grp78 的诱导来抑制 ER 应激诱导的细胞凋亡
DOI：
10.1038/labinvest.2014.63
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发表时间：
2014-08-01
影响因子：
5
通讯作者：
Luo, Zhuo-Jing
中科院分区：
文献类型：
--
作者：
Guo, Yun-Shan;Sun, Zhen;Luo, Zhuo-Jing
虽然许多研究表明雌激素预防绝经后骨丢失部分是由于其抗成骨细胞凋亡作用，但其潜在机制尚未完全阐明。在本研究中，我们发现，17 β-雌二醇（17 β-E-2），一种主要的雌激素，抑制内质网（ER）应激诱导的MC 3 T3-E1细胞和原代成骨细胞凋亡。有趣的是，17 β-E-2-促进Grp 78诱导，但不响应ER应激的CHOP诱导。我们进一步证实了Grp 78特异性siRNA通过激活caspase-12和caspase-3逆转了17 β-E-2对ER应激诱导的细胞凋亡的抑制。此外，我们发现，17 β-E-2显着增加磷酸化TFII-I水平和核定位的TFII-I在ER应激条件。在TFII-I存在下，17 β-E-2以剂量依赖性方式刺激Grp 78启动子活性，并增强TFII-I与Grp 78启动子的结合。此外，17 β-E-2显著增加MC 3 T3-E1细胞中磷酸化ERK 1/2水平和Ras激酶活性。ERK 1/2活性特异性抑制剂U 0126显著阻断17 β-E-2诱导的TFII-I磷酸化和Grp 78表达。总之，17 β-E-2通过促进Ras-ERK 1/2-TFII-I信号通路依赖性Grp 78诱导来保护MC 3 T3-E1细胞免受ER应激诱导的凋亡。
Although many studies have suggested that estrogen prevents postmenopausal bone loss partially due to its anti-apoptosis effects in osteoblasts, the underlying mechanism has not been fully elucidated. In the present study, we found that 17 beta-estradiol (17 beta-E-2), one of the primary estrogens, inhibited endoplasmic reticulum (ER) stress-induced apoptosis in MC3T3-E1 cells and primary osteoblasts. Interestingly, 17 beta-E-2-promoted Grp78 induction, but not CHOP induction in response to ER stress. We further confirmed that Grp78-specific siRNA reversed the inhibition of 17 beta-E-2 on ER stress-induced apoptosis by activating caspase-12 and caspase-3. Moreover, we found that 17 beta-E-2 markedly increased the phosphorylated TFII-I levels and nuclear localization of TFII-I in ER stress conditions. 17 beta-E-2 stimulated Grp78 promoter activity in a dose-dependent manner in the presence of TFII-I and enhanced the binding of TFII-I to the Grp78 promoter. In addition, 17 beta-E-2 notably increased phosphorylated ERK1/2 levels and Ras kinase activity in MC3T3-E1 cells. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked 17 beta-E-2-induced TFII-I phosphorylation and Grp78 expression in response to ER stress. Together, 17 beta-E-2 protected MC3T3-E1 cells against ER stress-induced apoptosis by promoting Ras-ERK1/2-TFII-I signaling pathway-dependent Grp78 induction.