Mechanism of hypoxia-induced GCM1 degradation: implications for the pathogenesis of preeclampsia.
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.
Chiang
Meng-Hsiu
MH
Graduate Institute of Biochemical Sciences, National Taiwan University, and Division of High Risk Pregnancy, Mackay Memorial Hospital, Taipei, Taiwan.
Liang
Feng-Yu
FY
Chen
Chie-Pein
CP
Chang
Ching-Wen
CW
Cheong
Mei-Leng
ML
Wang
Liang-Jie
LJ
Liang
Ching-Yeu
CY
Lin
Fang-Yu
FY
Chou
Chih-Chine
CC
Chen
Hungwen
H
D018692:Antimanic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005260:Female; D005455:Fluorescent Antibody Technique; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D018021:Lithium Chloride / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination
D018692:Antimanic Agents; D004268:DNA-Binding Proteins; D015686:Gene Products, env; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D044843:SKP Cullin F-Box Protein Ligases; D014157:Transcription Factors; C491089:GCM1 protein, human; C405335:syncytin; C000605506:GSK3B protein, human