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-3␤ activation. Activated GSK-3␤ phosphorylates GCM1 on Ser 322 , which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3␤ 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.Trophoblast invasion, fetoplacental vascular development, and maternal vascular remodeling are key events for the formation of the hemochorial placenta in humans. Human placental trophoblasts make direct contact with maternal blood to mediate efficient gas and nutrient exchange between mother and fetus. It is evident that failure in the aforementioned key events will compromise placental function and have a significant impact on the health of both fetus and mother. Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies worldwide. The clinical features of preeclampsia include hypertension, proteinuria, and edema. Although the etiologic factors of preeclampsia are currently unknown, shallow trophoblast invasion and poor maternal vascular remodeling have been reported in preeclamptic placentas. It is thought that these defects impair the development of the fetal-maternal vasculature and result in placental ischemia and hypoxia, which contribute to the pathogenesis of preeclampsia (1-3). Consistent with this model, expression of the antiangiogenic protein soluble Flt-1 (Fms-like tyrosine kinase-1) (sFlt-1) 3 is elevated, whereas expression of the proangiogenic vascular endothelial growth factor (VEGF) and placental growth factor (PGF) is decreased in preeclampsia (4, 5). Systematic surveys of pregnant women have further revealed that the ratio between the circulating levels of sFlt-1 and PGF increases significantly prior to the onset of preeclampsia (6, 7). Therefore, an imbalance between pro-and antiangiogenic factors may be a contributing factor in preeclampsia pathogenesis.GCM1 (also known as GCMa) is a key transcription factor in placental development. Genetic ablation of mouse GCM1 is embryonically lethal due to failure of the formation of the labyrinth layer and the fusion of trophoblasts to syncyti...

Glial cell missing Drosophila homolog a (GCMa) is an essential transcription factor for placental development, which controls the differentiation of the syncytiotrophoblast layer. Although the activity of GCMa can be post-translationally regulated by protein phosphorylation, ubiquitination, and acetylation, it is unknown whether GCMa activity can be regulated by sumoylation. In this report, we investigated the role of sumoylation in the regulation of GCMa activity. We demonstrated that Ubc9, the E2 component of the sumoylation machinery, specifically interacts with the N-terminal domain of GCMa and promotes GCMa sumoylation on lysine 156. Moreover, GCMa-mediated transcriptional activation was repressed by sumoylation but was enhanced in the presence of the SUMO-specific protease, SENP1. The repressive effect of sumoylation on GCMa transcriptional activity was attributed to decreased DNA binding activity of GCMa. Furthermore, structural analysis revealed a steric clash between the SUMO1 moiety of sumoylated GCMa and the DNA-binding surfaces of GCMa, which may destabilize the interaction between GCMa and its cognate DNA sequence. Our study demonstrates that GCMa is a new sumoylation substrate and its activity is down-regulated by sumoylation.