Mechanism of Hypoxia-induced GCM1 Degradation

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-3β activation. Activated GSK-3β phosphorylates GCM1 on Ser322, which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3β 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. 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-3β activation. Activated GSK-3β phosphorylates GCM1 on Ser322, which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3β 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 (1Maynard S. Epstein F.H. Karumanchi S.A. Annu. Rev. Med. 2008; 59: 61-78Crossref PubMed Scopus (252) Google Scholar, 2Wulff C. Weigand M. Kreienberg R. Fraser H.M. Reproduction. 2003; 126: 569-577Crossref PubMed Scopus (84) Google Scholar, 3Soleymanlou N. Jurisica I. Nevo O. Ietta F. Zhang X. Zamudio S. Post M. Caniggia I. J. Clin. Endocrinol. Metab. 2005; 90: 4299-4308Crossref PubMed Scopus (307) Google Scholar). Consistent with this model, expression of the antiangiogenic protein soluble Flt-1 (Fms-like tyrosine kinase-1) (sFlt-1) 3The abbreviations used are: sFlt-1soluble Flt-1VEGFvascular endothelial growth factorPGFplacental growth factorsiRNAsmall interfering RNAmAbmonoclonal antibodyPMSFphenylmethylsulfonyl fluorideHAhemagglutininCTBcytotrophoblastPI3Kphosphatidylinositol 3-kinaseWTwild typeKDkinase-deadCAconstitutively activeHIFhypoxia-inducible factorARNTarylhydrocarbon receptor nuclear translocatorE2ubiquitin carrier proteinE3ubiquitin-protein isopeptide ligaseUbubiquitin. is elevated, whereas expression of the proangiogenic vascular endothelial growth factor (VEGF) and placental growth factor (PGF) is decreased in preeclampsia (4Torry D.S. Wang H.S. Wang T.H. Caudle M.R. Torry R.J. Am. J. Obstet. Gynecol. 1998; 179: 1539-1544Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 5Wikström A.K. Larsson A. Eriksson U.J. Nash P. Nordén-Lindeberg S. Olovsson M. Obstet. Gynecol. 2007; 109: 1368-1374Crossref PubMed Scopus (153) Google Scholar). 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 (6Simas T.A. Crawford S.L. Solitro M.J. Frost S.C. Meyer B.A. Maynard S.E. MooreAm. J. Obstet. Gynecol. 2007; 197: 244.e1-244.e8Abstract Full Text Full Text PDF Scopus (160) Google Scholar, 7Levine R.J. Lam C. Qian C. Yu K.F. Maynard S.E. Sachs B.P. Sibai B.M. Epstein F.H. Romero R. Thadhani R. Karumanchi S.A. N. Engl. J. Med. 2006; 355: 992-1005Crossref PubMed Scopus (1505) Google Scholar). Therefore, an imbalance between pro- and antiangiogenic factors may be a contributing factor in preeclampsia pathogenesis. soluble Flt-1 vascular endothelial growth factor placental growth factor small interfering RNA monoclonal antibody phenylmethylsulfonyl fluoride hemagglutinin cytotrophoblast phosphatidylinositol 3-kinase wild type kinase-dead constitutively active hypoxia-inducible factor arylhydrocarbon receptor nuclear translocator ubiquitin carrier protein ubiquitin-protein isopeptide ligase ubiquitin. 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 syncytiotrophoblasts (8Anson-Cartwright L. Dawson K. Holmyard D. Fisher S.J. Lazzarini R.A. Cross J.C. Nat. Genet. 2000; 25: 311-314Crossref PubMed Scopus (344) Google Scholar, 9Schreiber J. Riethmacher-Sonnenberg E. Riethmacher D. Tuerk E.E. Enderich J. Bösl M.R. Wegner M. Mol. Cell. Biol. 2000; 20: 2466-2474Crossref PubMed Scopus (165) Google Scholar). Human GCM1 positively regulates syncytin 1 and PGF gene expression, which is critical for trophoblastic fusion and placental vasculogenesis (10Yu C. Shen K. Lin M. Chen P. Lin C. Chang G.D. Chen H. J. Biol. Chem. 2002; 277: 50062-50068Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 11Chang M. Mukherjea D. Gobble R.M. Groesch K.A. Torry R.J. Torry D.S. Biol. Reprod. 2008; 78: 841-851Crossref PubMed Scopus (52) Google Scholar). Interestingly, decreased expression of GCM1 as well as its target genes, syncytin 1 and PGF, have been observed in preeclampsia and in placental cells under hypoxia (4Torry D.S. Wang H.S. Wang T.H. Caudle M.R. Torry R.J. Am. J. Obstet. Gynecol. 1998; 179: 1539-1544Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 11Chang M. Mukherjea D. Gobble R.M. Groesch K.A. Torry R.J. Torry D.S. Biol. Reprod. 2008; 78: 841-851Crossref PubMed Scopus (52) Google Scholar, 12Munaut C. Lorquet S. Pequeux C. Blacher S. Berndt S. Frankenne F. Foidart J.M. Hum. Reprod. 2008; 23: 1407-1415Crossref PubMed Scopus (104) Google Scholar, 13Chen C.P. Chen C.Y. Yang Y.C. Su T.H. Chen H. Placenta. 2004; 25: 413-421Crossref PubMed Scopus (98) Google Scholar, 14Chen C.P. Wang K.G. Chen C.Y. Yu C. Chuang H.C. Chen H. BJOG. 2006; 113: 152-158Crossref PubMed Scopus (79) Google Scholar, 15Li H. Gu B. Zhang Y. Lewis D.F. Wang Y. Placenta. 2005; 26: 210-217Crossref PubMed Scopus (142) Google Scholar). Since hypoxia caused by incomplete trophoblast invasion and impaired spiral arterial remodeling is associated with preeclampsia (16Redman C.W. Sargent I.L. Science. 2005; 308: 1592-1594Crossref PubMed Scopus (2067) Google Scholar, 17Brosens I.A. Robertson W.B. Dixon H.G. Obstet. Gynecol. Annu. 1972; 1: 177-191PubMed Google Scholar), we speculated that decreased GCM1 activity contributes to the pathogenesis of preeclampsia. To better understand the role of GCM1 in the pathogenesis of preeclampsia, we have investigated the molecular mechanism by which hypoxia decreases GCM1 expression. We show here that the PI3K-Akt pathway is inactivated under hypoxia, which results in activation of GSK-3β in placental cells. Activated GSK-3β phosphorylates the Ser322 residue in GCM1 and promotes GCM1 ubiquitination and degradation via the SCFFBW2 E3 ligase. Importantly, hypoxia-induced GCM1 degradation was blocked by pharmacological inhibition of GSK-3β by LiCl. Moreover, we demonstrate that GCM1 positively autoregulates its own promoter activity, forming a positive feedback cascade that activates gene expression critical for placental development. Therefore, GCM1 degradation induced by hypoxia would result in profound decrease in expression of GCM1 target genes, contributing to preeclampsia. Our results delineate the signaling pathway responsible for hypoxia-induced GCM1 degradation, which could play a critical role in the pathogenesis of preeclampsia and offer potential novel therapeutic opportunity. The expression plasmids, pHA-GCM1, pGCM1-FLAG, pFBW2-Myc, and pHA-Ub, have been described previously (18Yang C.S. Yu C. Chuang H.C. Chang C.W. Chang G.D. Yao T.P. Chen H. J. Biol. Chem. 2005; 280: 10083-10090Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). The expression plasmids for mutant HA-GCM1 and GCM1-FLAG with site-specific mutation were constructed by two-step PCR. The expression plasmids for Myc-tagged GSK-3β-wild type (WT), GSK-3β-constitutively active (CA), and GSK-3β-kinase-dead (KD) were kindly provided by Dr. Mien-Chie Hung (University of Texas M.D. Anderson Cancer Center). The expression plasmids, pMyc-p110*, pHA-myr-Akt, and pAkt-KA, have been described previously (19Huang W.C. Chen C.C. Mol. Cell. Biol. 2005; 25: 6592-6602Crossref PubMed Scopus (221) Google Scholar). The reporter plasmid, p(GBS)4E1BLuc, has been described previously (20Chang C.W. Chuang H.C. Yu C. Yao T.P. Chen H. Mol. Cell. Biol. 2005; 25: 8401-8414Crossref PubMed Scopus (80) Google Scholar). 293T, BeWo, and JAR cells were obtained from the American Type Culture Collection (Manassas, VA). Stable BeWo cells expressing HA-tagged GCM1 (BeWo31) were established as previously described (18Yang C.S. Yu C. Chuang H.C. Chang C.W. Chang G.D. Yao T.P. Chen H. J. Biol. Chem. 2005; 280: 10083-10090Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). 293T cells were maintained at 37 °C in minimal essential medium α medium, with 10% fetal bovine serum, 100 mg/ml streptomycin, and 100 units/ml penicillin. JAR, BeWo, and BeWo31 were maintained at 37 °C in F-12K medium supplemented with 15% fetal bovine serum and the aforementioned antibiotics. Isolation and purification of villous cytotrophoblast (CTB) cells from term placentas was performed according to Kliman et al. (21Kliman H.J. Nestler J.E. Sermasi E. Sanger J.M. Strauss 3rd, J.F. Endocrinology. 1986; 118: 1567-1582Crossref PubMed Scopus (1408) Google Scholar). Purified CTB cells were maintained at 37 °C in Iscove's modified Dulbecco's medium containing 10% heat-inactivated fetal bovine serum and the aforementioned antibiotics. For transient expression, 293T cells were transfected with expression plasmid(s) using the calcium phosphate coprecipitation method. Transfection of siRNA into 293T cells was performed with the TransIT TKO reagent (Mirus, Madison, WI). Hypoxia was achieved by exposing cells to 1% O2, 5% CO2, and 94% N2 in a multigas incubator (Astec, Fukuoka, Japan) or to 250 μm CoCl2, an agent with effects that mimic hypoxic conditions, whereas normoxia was achieved with 21% O2, 5% CO2, and balanced N2. For in vivo ubiquitination assays of GCM1, 293T cells were transfected with pGCM1-FLAG, pHA-Ub, and the indicated GSK-3β expression plasmid or siRNA (Santa Cruz Biotechnology, Inc., Santa by with of the GCM1 was performed by using monoclonal antibody and by using as previously described (18Yang C.S. Yu C. Chuang H.C. Chang C.W. Chang G.D. Yao T.P. Chen H. J. Biol. Chem. 2005; 280: 10083-10090Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). and were obtained from was obtained from to Ser322 and were and in The were further the To study the of GSK-3β on GCM1 or the of GCM1 and its the or 293T cells were transfected with the indicated expression plasmid and siRNA as described in the cells were with or LiCl and for the indicated of and for with the indicated were by using an and was used to for between of was RNA was using and into using with an of GCM1 was in the using a reagent The of were and for and for GCM1, and for and and for were and in for was performed as previously described C.P. Chen C.Y. Yang Y.C. Su T.H. Chen H. Placenta. 2004; 25: 413-421Crossref PubMed Scopus (98) Google Scholar). In the were blocked with protein for and with the antibody in for 1 at in for were with antibody for 1 at by was under a with a and For 293T cells were transfected with the indicated or mutant cells were in the 1 1 phenylmethylsulfonyl and a inhibitor The was with or to in the at °C for with the The were by with and to the of GCM1 were and with For 293T cells were transfected with the indicated F-box protein expression were and with the indicated to under described the were by with The development of preeclampsia is associated with placental hypoxia and a of the GCM1 transcription To GCM1 is a critical target of placental hypoxia, we investigated the effects of hypoxia on GCM1 expression in the placental JAR and BeWo, and in a BeWo (BeWo31) expressing HA-tagged GCM1 under the The levels of GCM1 in the were significantly decreased under hypoxia with a in GCM1 protein levels Interestingly, the protein of HA-GCM1 by the promoter in BeWo31 cells was decreased under hypoxia or in the of the hypoxia was due to a of hypoxia on the levels of HA-GCM1 were in and cells by were in BeWo of the HA-GCM1 protein in the BeWo31 that the of hypoxia on GCM1 is Importantly, the hypoxia-induced of GCM1 could be by the that GCM1 is by the in to hypoxia In a study of GCM1 gene expression, we that GCM1 its own promoter activity Therefore, hypoxia would GCM1 degradation and further GCM1 activity by the positive feedback of GCM1 gene expression, leading to a of GCM1 transcription have that to hypoxic activates or the PI3K-Akt signaling pathway, on the type M. A. J. A. L. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, D. Y. C. N. M. C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). To PI3K-Akt signaling pathway a role in hypoxia associated with preeclampsia, we the effects of hypoxia on the villous CTB cells from term placentas and in placental in the levels of the and were significantly decreased in CTB cells and under hypoxia for that hypoxia may the activity of the an inhibitor of significantly decreased the HA-GCM1 protein in BeWo31 under normoxia whereas an the HA-GCM1 protein under In of this the expression of constitutively active of and and were to whereas the mutant of activation be to of GCM1-FLAG by and the protein of GCM1-FLAG was in the of and decreased in the of these results that of the PI3K-Akt pathway by hypoxia promotes GCM1 degradation. phosphorylates the residue of GSK-3β and GSK-3β activity D. A. C. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar), we GSK-3β regulates GCM1 under normoxia and of the GSK-3β in BeWo, JAR, and CTB cells significantly under hypoxia, whereas levels of the active GSK-3β were Therefore, GSK-3β activity is under hypoxic and may be associated with GCM1 in placental cells. with a GSK-3β was to significantly HA-GCM1 in cells with or to hypoxia Since placental hypoxia is associated with preeclampsia, the expression of GCM1 and in preeclamptic placentas was with that in placentas by In with study C.P. Chen C.Y. Yang Y.C. Su T.H. Chen H. Placenta. 2004; 25: 413-421Crossref PubMed Scopus (98) Google Scholar), expression of GCM1 was decreased in preeclamptic placentas Interestingly, the expression of in preeclamptic placentas was decreased with that in placentas Therefore, a GSK-3β activity in preeclamptic placentas may be responsible for the GCM1 protein in preeclampsia. We GSK-3β regulates GCM1 which GCM1 to for degradation (18Yang C.S. Yu C. Chuang H.C. Chang C.W. Chang G.D. Yao T.P. Chen H. J. Biol. Chem. 2005; 280: 10083-10090Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). In vivo ubiquitination of GCM1 was in 293T cells with pHA-Ub, pGCM1-FLAG, and an expression plasmid the kinase-dead (KD) or constitutively active on the in the of GCM1-FLAG was decreased in the of the In the GSK-3β with a GSK-3β an prevented GCM1 ubiquitination to protein we further that the of GCM1-FLAG was to in the or GSK-3β cells in the or cells results that active GSK-3β promotes GCM1 ubiquitination and degradation. of GCM1 on potential GSK-3β in GCM1 were and in in vivo ubiquitination assays in to the GSK-3β in in Ser322 or into and significantly impaired GCM1 Moreover, the of both and the mutant the mutation of Ser322 and were significantly The F-box FBW2, is the of the SCFFBW2 E3 ligase responsible for GCM1 ubiquitination (18Yang C.S. Yu C. Chuang H.C. Chang C.W. Chang G.D. Yao T.P. Chen H. J. Biol. Chem. 2005; 280: 10083-10090Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). We investigated of GCM1 by on the of Ser322 and In with and from 293T cells expressing or mutant GCM1-FLAG an or mutation in Ser322 and between and the and was with the GCM1-FLAG and the mutant Ser322 was into a GCM1 of or Ser322 and were for with F-box FBW2, and in of the F-box in 293T cells. a both and was an with was observed Therefore, of Ser322 and a in GCM1 that with site-specific were to the of Ser322 and and in GCM1 we that GSK-3β is in Ser322 in GCM1 in the of was significantly decreased in and 293T cells We further that hypoxia Ser322 in BeWo31 placental cells which could be by LiCl a of GSK-3β for Ser322 under results were observed in JAR cells expressing HA-GCM1 Interestingly, the of was significantly in BeWo31 cells under normoxia or hypoxia Therefore, is to be constitutively and to function as the phosphate for of Ser322 in GCM1 in placental cells. these results that of Ser322 and in GCM1 is critical for its degradation under GCM1 is a critical transcription factor for placental development and have that GCM1 expression is decreased in preeclamptic placentas and placental cells under hypoxia C.P. Chen C.Y. Yang Y.C. Su T.H. Chen H. Placenta. 2004; 25: 413-421Crossref PubMed Scopus (98) Google Scholar, I. C. K. R. J. S. 2005; PubMed Scopus Google Scholar). on these we to in the present study how hypoxia regulates GCM1 expression in the of the major to hypoxia is expression of genes in and by hypoxia-inducible factors is a transcription factor of and the arylhydrocarbon receptor nuclear translocator known as Interestingly, have indicated that and are for placental development M. A. E. 2000; PubMed Scopus Google Scholar, E. P. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar). of trophoblast cells from and placentas further that is in the of trophoblast cells. In cells into syncytiotrophoblasts M. A. E. 2000; PubMed Scopus Google Scholar, E. P. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, E. K. Fisher S.J. 2005; PubMed Scopus Google Scholar). we investigated the role of in GCM1 gene expression this study was and direct of on GCM1 gene expression we that GCM1 autoregulates its promoter activity we that hypoxia GCM1 activity at both and levels by GCM1 degradation have that degradation of receptor α is induced by hypoxia via between receptor α and M. B. M. D. R. S. Mol. Endocrinol. 2002; PubMed Scopus Google Scholar, J. D. S. Y. Mol. Endocrinol. 2005; PubMed Scopus Google Scholar). We the of between GCM1 and and between and GCM1 Moreover, we have hypoxia regulates GCM1 degradation activation of and gene expression, which are the E3 and for the degradation of GCM1, Chen Chen H. Biol. Reprod. 2008; PubMed Scopus Google Scholar). Our results indicated that expression of the and genes was by hypoxia GCM1 autoregulates its own expression and hypoxia GCM1 degradation, the BeWo31 placental cells expressing HA-GCM1 provided a for further study of hypoxia-induced GCM1 degradation at the expression of HA-GCM1 is by the activity is by We to the hypoxia signaling pathway is in the of GCM1 on the hypoxia activates or the PI3K-Akt signaling For the pathway is in and cells M. A. J. A. L. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, Cancer Google Scholar, D. Cell. PubMed Scopus Google and inactivated in cells D. Y. C. N. M. C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. C. Mol. Cell. Biol. 2007; PubMed Scopus Google under Although the mechanism of activation or inhibition of the PI3K-Akt signaling pathway by hypoxia is in the present we that this pathway is in BeWo, and JAR placental cells and cytotrophoblast cells under hypoxia We further that the of the of is decreased the PI3K-Akt signaling pathway is by hypoxia or in preeclamptic placentas. the GSK-3β phosphorylates Ser322 in GCM1 and promotes GCM1 degradation. Our results are in with a study by et al. S. D. B.A. I. D.S. Am. J. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), in which of and activation of GSK-3β were to be associated with protein inhibition and in placentas of growth and preeclampsia. Therefore, GSK-3β is a target of placental and GSK-3β is to cause of protein and degradation in the pathogenesis of growth and preeclampsia. and at the residue of of type 1 and expression of factors and are all to preeclampsia (1Maynard S. Epstein F.H. Karumanchi S.A. Annu. Rev. Med. 2008; 59: 61-78Crossref PubMed Scopus (252) Google Scholar, J.M. Reprod. 2007; PubMed Scopus Google Scholar). In have that both in in and of type 1 receptor into pregnant result in the development of preeclampsia C.C. Zhang Y. R.A. Zhang H. M.J. Y. Nat. Med. 2008; PubMed Scopus Google Scholar, K. K. H. S. Y. L. S. H.G. J. Strauss J.F. R. 2008; PubMed Scopus Google Scholar). that factors are associated with preeclampsia, and its are is that the pathogenesis of this and of of these to placental and development of the of PGF and was in villous trophoblasts and may formation in the K. P. of the Human Placenta. Scholar, Y. M. K. M. J. K. C. Fisher S.J. Am. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). PGF and expression was in the which and the endothelial cells in spiral to maternal vascular remodeling Y. M. Fisher S.J. Biol. 2003; PubMed Scopus Google Scholar). circulating levels of and PGF have been in preeclampsia and may for endothelial in preeclampsia (6Simas T.A. Crawford S.L. Solitro M.J. Frost S.C. Meyer B.A. Maynard S.E. MooreAm. J. Obstet. Gynecol. 2007; 197: 244.e1-244.e8Abstract Full Text Full Text PDF Scopus (160) Google Scholar, 7Levine R.J. Lam C. Qian C. Yu K.F. Maynard S.E. Sachs B.P. Sibai B.M. Epstein F.H. Romero R. Thadhani R. Karumanchi S.A. N. Engl. J. Med. 2006; 355: 992-1005Crossref PubMed Scopus (1505) Google Scholar). fusion is essential for the of the syncytiotrophoblast which the syncytin 1 and is a placental protein with an activity M. M. I. O. C. A. B. 2007; PubMed Scopus Google Scholar). of syncytin is by GCM1 and is decreased in preeclampsia C.P. Chen Yang Chen C.Y. C.C. Chang G.D. Chen H. Biol. Reprod. 2008; PubMed Scopus Google Scholar). expression of both in hypoxic and preeclampsia may be responsible for the villous and trophoblast into the maternal in preeclampsia. under placental hypoxia of the genes by GCM1, as may contribute to placental leading to preeclampsia K. H. S. N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). on the signaling pathway hypoxia-induced GCM1 degradation, here we a for the role of GCM1 in the pathogenesis of preeclampsia. GCM1 is to degradation under placental GCM1 gene expression is due to impaired of GCM1 gene expression. feedback to a significant of GCM1 under GCM1 levels caused a failure in the expression of GCM1 target genes, in placental In the of proangiogenic factors and is to cause endothelial and formation of the syncytiotrophoblast layer in the preeclamptic placentas. a key placental transcription factor, the activity of GCM1 be by which may placental development and For the pathway is to of GCM1, which GCM1 ubiquitination and increases GCM1 activity (20Chang C.W. Chuang H.C. Yu C. Yao T.P. Chen H. Mol. Cell. Biol. 2005; 25: 8401-8414Crossref PubMed Scopus (80) Google Scholar). Here we have revealed a further pathway responsible for decreased GCM1 activity in placental cells under hypoxia activation of the pathway to GCM1 and pathway is to play an important role in the pathogenesis of preeclampsia and provides an for therapeutic in preeclampsia. We Dr. for with