Chiang Meng-Hsiu, Liang Feng-Yu, Chen Chie-Pein, Chang Ching-Wen, Cheong Mei-Leng, Wang Liang-Jie, Liang Ching-Yeu, Lin Fang-Yu, Chou Chih-Chine, Chen Hungwen
Graduate Institute of Biochemical Sciences, National Taiwan University, and Division of High Risk Pregnancy, Mackay Memorial Hospital, Taipei, Taiwan.
J Biol Chem. 2009 Jun 26;284(26):17411-9. doi: 10.1074/jbc.M109.016170. Epub 2009 May 5.
Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies worldwide. Although hypoxia caused by incomplete trophoblast invasion and impaired spiral arterial remodeling is thought to be a major cause of preeclampsia, how hypoxia affects placental development remains uncertain. GCM1 (glial cells missing homolog 1) is a transcription factor critical for placental development. In preeclampsia, GCM1 and its target genes syncytin 1 and placental growth factor, important for syncytiotrophoblast formation and placental vasculogenesis, are all decreased. Here we present evidence that GCM1 is a major target of hypoxia associated with preeclampsia. We show that hypoxia triggers GCM1 degradation by suppressing the phosphatidylinositol 3-kinase-Akt signaling pathway, leading to GSK-3beta activation. Activated GSK-3beta phosphorylates GCM1 on Ser322, which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3beta inhibitor LiCl prevented hypoxia-induced GCM1 degradation. Our study identifies a molecular basis for the disrupted GCM1 transcription network in preeclampsia and provides a potential avenue for therapeutic intervention.
子痫前期是一种主要的妊娠特异性疾病，影响全球5%-7%的妊娠。尽管由滋养层细胞不完全浸润和螺旋动脉重塑受损引起的缺氧被认为是子痫前期的主要原因，但缺氧如何影响胎盘发育仍不确定。胶质细胞缺失同源物1（GCM1）是一种对胎盘发育至关重要的转录因子。在子痫前期，对合体滋养层细胞形成和胎盘血管生成很重要的GCM1及其靶基因——合胞素1和胎盘生长因子均减少。在此，我们提供证据表明GCM1是与子痫前期相关的缺氧的主要靶点。我们发现缺氧通过抑制磷脂酰肌醇3激酶-蛋白激酶B信号通路触发GCM1降解，导致糖原合成酶激酶3β（GSK-3β）激活。激活的GSK-3β使GCM1的丝氨酸322位点磷酸化，进而募集F-box蛋白FBW2，导致GCM1泛素化和降解。重要的是，GSK-3β抑制剂氯化锂可防止缺氧诱导的GCM1降解。我们的研究确定了子痫前期中GCM1转录网络破坏的分子基础，并为治疗干预提供了一条潜在途径。
