Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Mechanism of hypoxia-induced GCM1 degradation: implications for the pathogenesis of preeclampsia. 1941 64