Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimanic Agents / pharmacology
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Cells, Cultured
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DNA-Binding Proteins
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Female
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Fluorescent Antibody Technique
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Gene Products, env / genetics
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Gene Products, env / metabolism
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Hypoxia / metabolism*
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Immunoblotting
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Immunoenzyme Techniques
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Immunoprecipitation
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Lithium Chloride / pharmacology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Placenta / metabolism*
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Pre-Eclampsia / genetics
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Pre-Eclampsia / metabolism*
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Pre-Eclampsia / pathology
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Pregnancy
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Pregnancy Proteins / genetics
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Pregnancy Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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SKP Cullin F-Box Protein Ligases / genetics
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SKP Cullin F-Box Protein Ligases / metabolism
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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Ubiquitination
Substances
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Antimanic Agents
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DNA-Binding Proteins
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GCM1 protein, human
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Gene Products, env
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Nuclear Proteins
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Pregnancy Proteins
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RNA, Messenger
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Transcription Factors
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syncytin
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SKP Cullin F-Box Protein Ligases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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Lithium Chloride