Affinage

GCM1

Chorion-specific transcription factor GCMa · UniProt Q9NP62

Length
436 aa
Mass
49.3 kDa
Annotated
2026-04-28
58 papers in source corpus 33 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCM1 is a placenta-specific transcription factor that serves as a master regulator of trophoblast differentiation, controlling both syncytiotrophoblast fusion and extravillous trophoblast invasion. It transcriptionally activates key fusogenic and placental genes—including syncytin-1, syncytin-2, MFSD2A, HtrA4, WNT10B, CKMT1, and CDKN1C—through defined GCM1-binding sites in their promoters, and participates in a positive feedback loop with Fzd5/β-catenin signaling to direct chorionic branching morphogenesis (PMID:12397062, PMID:20484742, PMID:23610556, PMID:36442132). GCM1 protein stability and activity are governed by an intricate network of post-translational modifications: cAMP/PKA-stimulated CBP acetylation activates GCM1 and protects it from ubiquitination, whereas GSK-3β phosphorylation at Ser322 triggers SCF(FBW2)/UBE2D2-mediated proteasomal degradation, counterbalanced by DUSP23 dephosphorylation and RACK1-mediated competition for FBW2 binding; a parallel cAMP/Epac1/CaMKI cascade promotes SENP1-mediated desumoylation at Ser47 (PMID:16166624, PMID:15640526, PMID:19416964, PMID:20855292, PMID:21791615, PMID:23651062). GCM1 transcription itself is positively regulated by CREB/OASIS, Twist1, and Nanog, and negatively modulated by DREAM, p45NF-E2, and ΔNp63α, while protein-level inhibitors GATA3, DLX3, and caspase-14 proenzyme suppress its transactivation capacity (PMID:18495750, PMID:26992674, PMID:35338152, PMID:26899996, PMID:23580611). Genetic ablation of GCM1 in mice causes embryonic lethality due to failure of labyrinth layer development, establishing its essential role in placentation (PMID:10713170).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    The fundamental question of whether GCM1 is required for placental development was resolved: knockout mice die from failure of labyrinthine trophoblast differentiation, establishing GCM1 as essential for placentation.

    Evidence Gcm1 knockout mouse with histological and embryological analysis

    PMID:10713170

    Open questions at the time
    • Downstream transcriptional targets in the labyrinth were unknown
    • Mechanism by which GCM1 drives trophoblast differentiation was uncharacterized
    • Human relevance not directly tested
  2. 2002 High

    The first direct transcriptional target linking GCM1 to cell fusion was identified: GCM1 activates syncytin-1 expression through two binding sites upstream of the HERV-W 5'-LTR, explaining how GCM1 promotes syncytiotrophoblast formation.

    Evidence Reporter assay, adenoviral overexpression, and cell fusion assay in BeWo and JEG3 trophoblast cell lines

    PMID:12397062

    Open questions at the time
    • Other fusogenic target genes were not yet identified
    • Whether GCM1 is sufficient or only necessary for fusion was unclear
  3. 2003 Medium

    How GCM1 reaches the nucleus was resolved: nuclear import relies on two non-classical signals within the GCM domain and a C-terminal tyrosine-proline-rich region, counteracted by an N-terminal export activity.

    Evidence Domain deletion and fusion constructs with nuclear localization assays

    PMID:14572643

    Open questions at the time
    • Import receptors were not identified
    • Regulation of nuclear-cytoplasmic shuttling under physiological conditions was not addressed
  4. 2004 High

    GCM1 was shown to be both necessary and sufficient for syncytiotrophoblast lineage commitment: it promotes cell cycle exit in trophoblast stem cells, and antisense knockdown blocks syncytiotrophoblast differentiation.

    Evidence Ectopic expression and antisense knockdown in trophoblast stem cells with differentiation assays

    PMID:15196947

    Open questions at the time
    • Whether GCM1 also controls extravillous trophoblast fate was unknown
    • Downstream cell cycle targets were not identified
  5. 2005 High

    The mechanism controlling GCM1 protein turnover was established: the SCF(FBW2) E3 ubiquitin ligase targets GCM1 for proteasomal degradation in a phosphorylation-dependent manner, while cAMP/PKA-stimulated CBP acetylation at Lys367/406/409 stabilizes GCM1 by protecting it from ubiquitination.

    Evidence Co-IP, in vivo ubiquitination assay, RNAi of FBW2, in vitro acetylation assay, site-directed mutagenesis, and transcriptional reporter assays

    PMID:15640526 PMID:16166624

    Open questions at the time
    • The kinase responsible for the phosphorylation recognized by FBW2 was not yet identified
    • The E2 enzyme was unknown
  6. 2006 High

    The acetylation–deacetylation toggle was completed: HDAC3 directly deacetylates GCM1 and opposes CBP coactivation at the syncytin promoter, with forskolin-induced dissociation of HDAC3 enabling CBP recruitment.

    Evidence GST pull-down, Co-IP, ChIP at the syncytin promoter, reporter assay, TSA treatment

    PMID:16528103

    Open questions at the time
    • Whether other HDACs contribute was not tested
    • Structural basis of HDAC3–GCM1 interaction was not determined
  7. 2008 High

    The E2 enzyme UBE2D2 was identified as the conjugating enzyme working with SCF(FBW2), completing the ubiquitin-proteasome pathway for GCM1; separately, CREB and OASIS were identified as transcription factors that drive GCM1 gene expression through CRE sites in its promoter.

    Evidence In vitro ubiquitination reconstitution, RNAi of UBE2D2, pulse-chase; promoter mapping, EMSA, RNAi of CREB/OASIS in BeWo cells

    PMID:18495750 PMID:18703417

    Open questions at the time
    • Whether additional E2 enzymes contribute in vivo was not excluded
    • Signals that regulate CREB/OASIS upstream of GCM1 in placenta were not fully defined
  8. 2009 High

    The phosphorylation signal triggering FBW2 recognition was identified: hypoxia suppresses PI3K-Akt, activating GSK-3β to phosphorylate GCM1 at Ser322, which recruits FBW2 and initiates degradation—linking oxygen tension to GCM1 stability.

    Evidence Phosphorylation assay, Ser322 mutagenesis, Co-IP, ubiquitination assay, LiCl pharmacological rescue

    PMID:19416964

    Open questions at the time
    • Whether other phosphorylation sites cooperate with Ser322 was not resolved
    • In vivo hypoxia relevance in placental pathology was correlative
  9. 2010 High

    Two counterbalancing mechanisms were established: GCM1 directly activates syncytin-2 and MFSD2A (expanding the target gene repertoire beyond syncytin-1), and DUSP23 dephosphorylates Ser322 downstream of PKA-mediated Ser269/Ser275 phosphorylation, stabilizing and activating GCM1.

    Evidence EMSA, ChIP, bisulfite sequencing, cell fusion assay for targets; Co-IP, phosphorylation assay, RNAi of DUSP23

    PMID:20484742 PMID:20855292

    Open questions at the time
    • Whether DUSP23 regulation extends to other GCM1 phosphorylation sites was not tested
    • GCM1-mediated CpG demethylation mechanism was not fully characterized
  10. 2011 High

    A second cAMP-dependent activation axis was uncovered: cAMP/Epac1/CaMKI phosphorylates GCM1 at Ser47 to recruit the desumoylase SENP1, relieving sumoylation-mediated repression; separately, PKC/MEK/ERK-mediated phosphorylation at Ser328/378/383 was shown to promote GCM1 degradation.

    Evidence Co-IP, RNAi, phosphomimetic rescue, cell fusion assay; phosphorylation assay with site-directed mutagenesis and pharmacological inhibition

    PMID:21791615 PMID:22206674

    Open questions at the time
    • Crosstalk between sumoylation and ubiquitination pathways was not addressed
    • PKC/ERK degradation pathway was from a single lab
  11. 2013 High

    GCM1's role expanded beyond transcription: a Gcm1–Fzd5–β-catenin positive feedback loop was shown to drive chorionic branching morphogenesis; RACK1 was found to competitively inhibit FBW2-mediated GCM1 degradation; caspase-14 proenzyme was identified as a GCM1 inhibitor blocking CBP interaction.

    Evidence Conditional KO mice and tetraploid aggregation (Fzd5); AP-MS, Co-IP, RNAi, migration assay (RACK1); AP-MS, Co-IP, acetylation assay, cell fusion assay (caspase-14)

    PMID:23580611 PMID:23610556 PMID:23651062

    Open questions at the time
    • Whether RACK1 regulation is placenta-specific was unknown
    • Role of caspase-14 catalytic activity versus proenzyme form was not separated in vivo
  12. 2016 High

    Protein-level inhibition of GCM1 transactivation was broadened: GATA3 interacts with GCM1 and suppresses HtrA4 activation and trophoblast invasion without affecting DNA binding; Twist1 was identified as a transcriptional activator of GCM1 through intron 2 E-box elements.

    Evidence Co-IP with domain mapping, reporter assay, RNAi, invasion assay (GATA3); ChIP, siRNA, cell fusion assay (Twist1)

    PMID:26899996 PMID:26992674

    Open questions at the time
    • Whether GATA3 and DLX3 inhibition is additive or redundant was not tested
    • Twist1 regulation of GCM1 in primary trophoblasts was not confirmed
  13. 2017 High

    DLX3 was identified as another transcription factor that physically interacts with GCM1 and inhibits its transactivation, with co-occupancy at the PGF promoter producing antagonistic effects despite each factor independently activating PGF.

    Evidence Co-IP, mammalian one-hybrid, ChIP, reporter assay with mutagenesis

    PMID:27996093 PMID:28515447

    Open questions at the time
    • Physiological context determining DLX3–GCM1 balance in vivo was not defined
    • Other shared target genes were not systematically identified
  14. 2018 High

    GCM1's role in extravillous trophoblast migration was mechanistically linked to WNT signaling: GCM1 activates WNT10B transcription, which signals through FZD7 and Rac1 to promote cytoskeletal remodeling and migration, modulated by decidual SFRP3.

    Evidence Reporter assay, RNAi, migration/invasion assay, Co-IP, immunohistochemistry

    PMID:29979633

    Open questions at the time
    • Whether WNT10B–FZD7 axis is the sole mediator of GCM1-driven invasion was not established
    • In vivo invasion phenotype not directly tested
  15. 2022 High

    GCM1 was established as essential for both ST and EVT lineages in human trophoblast stem cells: GCM1 loss impairs EVT invasion, downregulates CDKN1C causing loss of contact inhibition, and GCM1 functionally antagonizes ΔNp63α to control stem cell–differentiation balance; CKMT1 was identified as a key GCM1 target for ST differentiation.

    Evidence RNAi/KO in human trophoblast stem cells, RNA-seq, ChIP-seq, invasion assay, reporter assay, Co-IP

    PMID:35338152 PMID:36442132 PMID:40280139

    Open questions at the time
    • Genome-wide direct versus indirect targets not fully delineated
    • Structural basis of ΔNp63α–GCM1 antagonism unknown
  16. 2025 Medium

    A non-coding RNA regulatory layer was identified: LINC01118 directly binds GCM1 protein, enhancing its stability and transcriptional activity and supporting GCM1 autoregulation during trophoblast fusion.

    Evidence RNA immunoprecipitation, Co-IP, overexpression/knockdown, cell fusion assay, transcriptomics

    PMID:41117589

    Open questions at the time
    • Mechanism by which lncRNA binding stabilizes GCM1 is unclear
    • Not independently replicated
    • Whether other lncRNAs similarly regulate GCM1 was not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of GCM1 DNA binding and post-translational modification crosstalk, the complete genome-wide direct target repertoire in human trophoblasts, and whether GCM1 mutations cause human placental disease.
  • No structural model of GCM1 exists
  • No human Mendelian disease linked by causative mutation
  • Crosstalk among acetylation, sumoylation, phosphorylation, and ubiquitination not systematically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
CBPDLX3DUSP23FBW2GATA3HDAC3RACK1SENP1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Genetic ablation of murine GCMa (mGCMa) causes embryonic lethality due to placental failure, specifically failure of the labyrinth layer to develop; labyrinthine trophoblasts fail to differentiate, establishing GCMa as essential for trophoblast differentiation and placental labyrinth formation. Knockout mouse model with histological and embryological analysis Molecular and cellular biology High 10713170
2002 GCMa transcriptionally activates syncytin gene expression via two GCMa-binding sites upstream of the 5'-LTR of the syncytin-harboring HERV-W family member in trophoblast cells, and adenovirus-directed GCMa expression enhances syncytin-mediated cell fusion in BeWo and JEG3 cells. Reporter assay, adenoviral overexpression, cell fusion assay in trophoblast cell lines The Journal of biological chemistry High 12397062
2004 Gcm1 promotes cell cycle exit and restricts trophoblast stem cells toward the syncytiotrophoblast fate; antisense Gcm1 blocks syncytiotrophoblast differentiation, demonstrating a necessary role for Gcm1 in syncytiotrophoblast lineage commitment. Ectopic expression, antisense knockdown in trophoblast stem cells with differentiation assays Developmental biology High 15196947
2005 The SCF(hFBW2) E3 ubiquitin ligase complex targets GCMa for proteasomal degradation; FBW2 interacts with GCMa in a phosphorylation-dependent manner and promotes GCMa ubiquitination; SKP1 and CUL1 associate with GCMa in vivo; RNAi knockdown of FBW2 reduces GCMa ubiquitination and increases its protein stability. Co-immunoprecipitation, in vivo ubiquitination assay, RNAi knockdown, pulse-chase The Journal of biological chemistry High 15640526
2005 cAMP/PKA signaling activates GCMa transcriptional activity by stimulating association of GCMa with CBP and increasing GCMa acetylation; CBP primarily acetylates GCMa at Lys367, Lys406, and Lys409 in the transactivation domain; acetylation protects GCMa from ubiquitination and increases TAD stability. In vitro acetylation assay, site-directed mutagenesis, Co-IP, ubiquitination assay, transcriptional reporter assay Molecular and cellular biology High 16166624
2005 Recombinant GCMa/1 protein produced from baculovirus-insect cell or E. coli systems exhibits specific transcriptional activity in vitro on G-free reporter constructs carrying GCMa-binding sites; a TATA box downstream of the proximal GBS in the syncytin promoter is essential for GCMa-directed transcriptional activation. In vitro transcription assay, recombinant protein, G-free reporter, mutagenesis Biochemistry and cell biology High 15864327
2005 cAMP/PKA signaling pathway acts upstream of GCMa; PKA overexpression upregulates GCMa transcriptional activity and both GCMa and syncytin transcripts, promoting trophoblast differentiation. Transient transfection, reporter assay, qRT-PCR in BeWo cells FEBS letters Medium 16004993
2006 HDAC3 directly interacts with GCMa and deacetylates it, counteracting CBP-mediated coactivation of GCMa transcriptional activity; HDAC3 associates with the proximal GCMa-binding site in the syncytin promoter and dissociates in the presence of forskolin, which promotes CBP and GCMa association at that site. GST pull-down, Co-IP, ChIP assay, transcriptional reporter assay, TSA treatment Nucleic acids research High 16528103
2007 GCMa regulates a set of murine placental target genes; integrin-alpha4, Rb1, and syncytin A are among the most strongly downregulated genes in GCMa-deficient chorionic tissue; promoter studies and in situ hybridization confirmed direct regulation of integrin-alpha4 and Rb1 by GCMa. Microarray of GCMa-deficient tissue, qRT-PCR verification, promoter reporter assay, in situ hybridization The Journal of biological chemistry High 18167345
2008 CREB and OASIS (bZIP transcription factors) bind to CRE sites in the GCMa promoter and stimulate GCMa transcription; TORC1 co-activates CREB-driven GCMa expression; knockdown of endogenous CREB or OASIS decreases GCMa mRNA and activity in BeWo trophoblast cells. Promoter mapping, EMSA, RNAi knockdown, reporter assay, overexpression Nucleic acids research High 18495750
2008 UBE2D2 is the E2 ubiquitin-conjugating enzyme that works with the SCF(FBXW2) E3 ligase complex to ubiquitinate GCM1; UBE2D2 enzyme activity is required for GCM1 ubiquitination; RNAi knockdown of UBE2D2 suppresses FBXW2-mediated GCM1 ubiquitination and prolongs GCM1 half-life in vivo. In vitro ubiquitination assay, Co-IP, RNAi knockdown, pulse-chase Biology of reproduction High 18703417
2009 Hypoxia triggers GCM1 degradation by suppressing the PI3K-Akt pathway, leading to GSK-3β activation; activated GSK-3β phosphorylates GCM1 on Ser322, which recruits the F-box protein FBW2, leading to GCM1 ubiquitination and proteasomal degradation; GSK-3β inhibitor LiCl prevents hypoxia-induced GCM1 degradation. Phosphorylation assay, site-directed mutagenesis, Co-IP, ubiquitination assay, pharmacological inhibition The Journal of biological chemistry High 19416964
2010 GCM1 directly activates syncytin 2 and MFSD2A gene expression in placental cells via functional GCM1-binding sites in their promoters; GCM1 also partly mediates CpG demethylation of the syncytin 2 promoter to enable expression; ectopic GCM1 expression in MCF-7 cells activates syncytin 2/MFSD2A and facilitates cell fusion. EMSA, ChIP assay, reporter assay, overexpression, bisulfite sequencing, cell fusion assay Biology of reproduction High 20484742
2010 Dual-specificity phosphatase 23 (DUSP23) interacts with GCM1 in a PKA-dependent manner (via phosphorylation of GCM1 at Ser269 and Ser275), reverses GSK-3β-mediated Ser322 phosphorylation, and thereby promotes GCM1 acetylation, stabilization, and activation; DUSP23 knockdown suppresses GCM1 target gene expression and placental cell fusion. Co-IP, phosphorylation assay, RNAi knockdown, cell fusion assay, reporter assay Nucleic acids research High 20855292
2011 A novel cAMP/Epac1/CaMKI signaling cascade regulates GCM1 sumoylation; Epac1 and Rap1 activate CaMKI to phosphorylate GCM1 at Ser47, facilitating interaction with the desumoylating enzyme SENP1 and leading to GCM1 desumoylation and activation; this promotes syncytin-1 and -2 expression and trophoblast cell fusion. Co-IP, RNAi, phosphomimetic mutant rescue, cell fusion assay, gene expression analysis Molecular and cellular biology High 21791615
2011 p45NF-E2 represses Gcm1 expression in trophoblast cells; in the absence of p45NF-E2, Gcm1 expression and acetylation are increased, leading to enhanced syncytiotrophoblast formation; this effect can be reversed by Gcm1 knockdown, placing p45NF-E2 upstream of Gcm1 in a regulatory axis controlling syncytiotrophoblast formation. Knockout mouse model, RNAi, acetylation assay, phenotypic rescue experiments Development (Cambridge, England) High 21558372
2013 DREAM (Downstream Regulatory Element Antagonist Modulator) directly interacts with the GCM1 promoter and represses GCM1-directed syncytiotrophoblast differentiation in a calcium-regulated manner; siRNA-mediated DREAM silencing upregulates GCM1 expression and reduces cytotrophoblast proliferation. EMSA, ChIP assay, siRNA knockdown, placental explant model PloS one High 23300953
2013 A positive feedback loop between Gcm1 and Fzd5 directs chorionic branching morphogenesis: Gcm1 upregulates Fzd5 at branching sites, and Fzd5 via nuclear β-catenin signaling maintains Gcm1 expression; Fzd5-mediated signaling induces disassociation of cell junctions (via downregulation of ZO-1, claudin 4, claudin 7) and upregulates Vegf expression in chorion trophoblast cells. Conditional KO mouse models, trophoblast stem cell lines, tetraploid aggregation assay, immunofluorescence PLoS biology High 23610556
2013 RACK1 interacts with FBW2 via WD repeats in both proteins and competes with GCM1 for FBW2 binding, thereby preventing GCM1 ubiquitination; RACK1 knockdown destabilizes GCM1, decreases expression of GCM1 target gene HTRA4, and reduces trophoblast cell migration and invasion. Tandem-affinity purification coupled with MS, Co-IP, RNAi knockdown, migration/invasion assay The Biochemical journal High 23651062
2013 Caspase-14 proenzyme interacts with GCM1 and suppresses its activity by impeding the interaction between GCM1 and CBP, thereby suppressing CBP-mediated GCM1 acetylation and transcriptional coactivation; caspase-14 knockdown increases GCM1 protein level and enhances syncytiotrophoblast differentiation. Tandem affinity purification coupled with MS, Co-IP, RNAi knockdown, acetylation assay, cell fusion assay FASEB journal High 23580611
2003 Nuclear localization of GCMa/Gcm-1 is mediated by two non-classical regions: the amino-terminal part of the GCM domain and a tyrosine-and-proline-rich carboxy-terminal region; nuclear import is counteracted by an amino-terminal nuclear export activity; GCMb/Gcm-2 uses a classical bipartite NLS. Domain deletion and fusion constructs with nuclear localization assays FEBS letters Medium 14572643
2004 Pitx transcription factors interact with GCMa via their conserved homeodomain binding to the DNA-binding domain of GCMa, resulting in cooperative DNA binding; Pitx proteins influence GCMa-dependent promoter activation in a cell-specific manner; Pitx2 colocalizes with GCMa in kidney. Co-IP, cooperative DNA binding assay, reporter assay, immunohistochemistry The Journal of biological chemistry Medium 15385555
2016 GATA3 interacts with GCM1 (but not GCM2) through the DNA-binding domain and first transcriptional activation domain of GCM1 and the transcriptional activation domains and zinc finger 1 of GATA3; GATA3 does not affect GCM1 DNA binding but suppresses GCM1 transcriptional activity and HtrA4 promoter activation; GATA3 knockdown elevates HtrA4 expression and enhances trophoblast invasion. Co-IP, reporter assay, RNAi knockdown, invasion assay, immunohistochemistry Scientific reports High 26899996
2016 Twist1 binds to the E-box-enriched region in intron 2 of the GCM1 gene during forskolin-induced trophoblast fusion, regulating GCM1 transcription; Twist1 siRNA knockdown inhibits BeWo cell fusion and downregulates GCM1 expression. ChIP assay, siRNA knockdown, cell fusion assay, qPCR/Western blot Placenta Medium 26992674
2017 DLX3 physically interacts with GCM1 and inhibits its transactivation activity; the DLX3 homeodomain is essential for DLX3-GCM1 interaction; co-overexpression of DLX3 and GCM1 antagonizes PGF promoter activity despite each independently activating it; both factors colocalize at the PGF promoter regulatory region. Co-IP, mammalian one-hybrid assay, ChIP assay, reporter assay, mutagenesis Scientific reports / Journal of cellular physiology High 27996093 28515447
2018 GCM1 promotes trophoblast cell migration through transcriptional activation of WNT10B; WNT10B signals through FZD7 to stimulate cytoskeletal remodeling via Rac1; decidual cell-secreted SFRP3 blocks FZD7-WNT10B interaction to reduce trophoblast migration. Reporter assay, RNAi knockdown, migration/invasion assay, Co-IP, immunohistochemistry FASEB journal High 29979633
2011 PMA induces GCMa phosphorylation via PKC- and MEK/ERK-dependent pathway at Ser328, Ser378, and Ser383, leading to GCMa degradation; PKC and MEK inhibitors prevent PMA-induced phosphorylation and degradation. Phosphorylation assay, site-directed mutagenesis, pharmacological inhibition, Western blot Biochemical and biophysical research communications Medium 22206674
2021 Folate deficiency promotes formation of a Gcm1/β-catenin/TCF4 complex that activates Wnt target gene transactivation through Wnt-responsive elements; Nanog upregulates Gcm1 transcription in mESCs under folate deficiency. Co-IP, reporter assay, ChIP, mouse NTD model, qPCR Cell death & disease Medium 33664222
2022 GCM1 is essential for both syncytiotrophoblast (ST) and extravillous trophoblast (EVT) differentiation; GCM1 knockdown in trophoblast stem cells reduces invasive capacity and alters EVT morphology; GCM1 regulates EVT differentiation partly by inducing expression of ASCL2 and the WNT antagonist NOTUM; ChIP-seq showed GCM1 binding near CDKN1C, and GCM1 loss causes downregulation of CDKN1C and loss of contact inhibition. RNAi knockdown, RNA sequencing, invasion assay, ChIP, trophoblast stem cell differentiation model PNAS / Stem cell reports High 36442132 40280139
2022 ΔNp63α and GCM1 functionally antagonize each other: ΔNp63α reduces GCM1 transcriptional activity, while GCM1 inhibits ΔNp63α oligomerization and autoregulation; EGF/CASVY cocktail activates ΔNp63α to partially inhibit GCM1 activity, enabling reversion to stem cell state; CKMT1 was identified as a key GCM1 target gene crucial for syncytiotrophoblast differentiation. Reporter assay, RNAi, overexpression, Co-IP, trophoblast stem cell induction model Nature communications High 35338152
2025 LINC01118 lncRNA directly interacts with GCM1 protein, enhancing its stability and transcriptional activity, and supports GCM1 autoregulation and downstream target gene expression required for trophoblast fusion. RNA immunoprecipitation, Co-IP, overexpression/knockdown, cell fusion assay, transcriptomics FASEB journal Medium 41117589

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 GCMa regulates the syncytin-mediated trophoblastic fusion. The Journal of biological chemistry 227 12397062
2000 Placental failure in mice lacking the mammalian homolog of glial cells missing, GCMa. Molecular and cellular biology 165 10713170
2006 The natural history of the WRKY-GCM1 zinc fingers and the relationship between transcription factors and transposons. Nucleic acids research 126 17130173
2004 The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to promote terminal differentiation of trophoblast stem cells. Developmental biology 123 15196947
1999 Murine Gcm1 gene is expressed in a subset of placental trophoblast cells. Developmental dynamics : an official publication of the American Association of Anatomists 121 10213386
2005 Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions. FEBS letters 112 16004993
2010 GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biology of reproduction 97 20484742
2013 A positive feedback loop involving Gcm1 and Fzd5 directs chorionic branching morphogenesis in the placenta. PLoS biology 83 23610556
2004 Complex patterns of GCM1 mRNA and protein in villous and extravillous trophoblast cells of the human placenta. Placenta 82 15135239
2005 Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa. Molecular and cellular biology 75 16166624
2022 The multifaceted role of GCM1 during trophoblast differentiation in the human placenta. Proceedings of the National Academy of Sciences of the United States of America 68 36442132
2009 Mechanism of hypoxia-induced GCM1 degradation: implications for the pathogenesis of preeclampsia. The Journal of biological chemistry 68 19416964
2006 Histone deacetylase 3 binds to and regulates the GCMa transcription factor. Nucleic acids research 65 16528103
1996 Gcm1, a mammalian homolog of Drosophila glial cells missing. FEBS letters 60 8814290
2012 Effects of reduced Gcm1 expression on trophoblast morphology, fetoplacental vascularity, and pregnancy outcomes in mice. Hypertension (Dallas, Tex. : 1979) 55 22275534
2020 SP1-activated long noncoding RNA lncRNA GCMA functions as a competing endogenous RNA to promote tumor metastasis by sponging miR-124 and miR-34a in gastric cancer. Oncogene 48 32439864
2005 FBW2 targets GCMa to the ubiquitin-proteasome degradation system. The Journal of biological chemistry 45 15640526
2011 A novel cyclic AMP/Epac1/CaMKI signaling cascade promotes GCM1 desumoylation and placental cell fusion. Molecular and cellular biology 43 21791615
2022 Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation. Nature communications 42 35338152
2002 Gcm1 expression defines three stages of chorio-allantoic interaction during placental development. Mechanisms of development 39 12049764
2016 GATA3 inhibits GCM1 activity and trophoblast cell invasion. Scientific reports 37 26899996
2008 bZIP-Type transcription factors CREB and OASIS bind and stimulate the promoter of the mammalian transcription factor GCMa/Gcm1 in trophoblast cells. Nucleic acids research 33 18495750
2010 Dual-specificity phosphatase 23 mediates GCM1 dephosphorylation and activation. Nucleic acids research 32 20855292
2002 Restricted expression of mouse GCMa/Gcm1 in kidney and thymus. Mechanisms of development 31 12351183
2016 Twist1 is involved in trophoblast syncytialization by regulating GCM1. Placenta 29 26992674
2011 p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth. Development (Cambridge, England) 29 21558372
2006 Increased plasma mRNAs of placenta-specific 1 (PLAC1) and glial cells-missing 1 (GCM1) in mothers with pre-eclampsia. Hiroshima journal of medical sciences 27 16594548
2005 Biochemical characterization of the human placental transcription factor GCMa/1. Biochemistry and cell biology = Biochimie et biologie cellulaire 26 15864327
2021 Induction of the PPARγ (Peroxisome Proliferator-Activated Receptor γ)-GCM1 (Glial Cell Missing 1) Syncytialization Axis Reduces sFLT1 (Soluble fms-Like Tyrosine Kinase 1) in the Preeclamptic Placenta. Hypertension (Dallas, Tex. : 1979) 25 34024123
2007 Identification of integrin-alpha4, Rb1, and syncytin a as murine placental target genes of the transcription factor GCMa/Gcm1. The Journal of biological chemistry 25 18167345
2009 CD9 regulates transcription factor GCM1 and ERVWE1 expression through the cAMP/protein kinase A signaling pathway. Reproduction (Cambridge, England) 23 19692500
2008 Ubiquitin-conjugating enzyme UBE2D2 is responsible for FBXW2 (F-box and WD repeat domain containing 2)-mediated human GCM1 (glial cell missing homolog 1) ubiquitination and degradation. Biology of reproduction 23 18703417
2013 DREAM mediated regulation of GCM1 in the human placental trophoblast. PloS one 22 23300953
2020 NPFF increases fusogenic proteins syncytin 1 and syncytin 2 via GCM1 in first trimester primary human cytotrophoblast cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 32501590
2017 p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction. Cell death & disease 17 28383551
2021 Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects. Cell death & disease 16 33664222
2017 Dlx3 and GCM-1 functionally coordinate the regulation of placental growth factor in human trophoblast-derived cells. Journal of cellular physiology 16 27996093
2013 RACK1 (receptor for activated C-kinase 1) interacts with FBW2 (F-box and WD-repeat domain-containing 2) to up-regulate GCM1 (glial cell missing 1) stability and placental cell migration and invasion. The Biochemical journal 16 23651062
2002 Ectopic expression of Gcm1 induces congenital spinal cord abnormalities. Development (Cambridge, England) 16 12135932
2004 Interaction, cooperative promoter modulation, and renal colocalization of GCMa and Pitx2. The Journal of biological chemistry 15 15385555
2017 Relevance of Wnt10b and activation of β-catenin/GCMa/syncytin-1 pathway in BeWo cell fusion. American journal of reproductive immunology (New York, N.Y. : 1989) 14 28370659
2000 Genomic organization, chromosomal localization, and the complete 22 kb DNA sequence of the human GCMa/GCM1, a placenta-specific transcription factor gene. Biochemical and biophysical research communications 13 11071865
2017 DLX3 interacts with GCM1 and inhibits its transactivation-stimulating activity in a homeodomain-dependent manner in human trophoblast-derived cells. Scientific reports 12 28515447
2019 Gcm1 is involved in cell proliferation and fibrosis during kidney regeneration after ischemia-reperfusion injury. Scientific reports 11 31133638
2011 A fetal variant in the GCM1 gene is associated with pregnancy induced hypertension in a predominantly hispanic population. International journal of molecular epidemiology and genetics 11 21915358
2018 SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 29979633
2013 Caspase-14 suppresses GCM1 acetylation and inhibits placental cell differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 23580611
2009 Hypoxia upregulates GCM1 in human placenta explants. Hypertension in pregnancy 10 19843007
2011 PMA induces GCMa phosphorylation and alters its stability via the PKC- and ERK-dependent pathway. Biochemical and biophysical research communications 8 22206674
2003 Structural requirements for nuclear localization of GCMa/Gcm-1. FEBS letters 6 14572643
2025 Hypoxia and loss of GCM1 expression prevent differentiation and contact inhibition in human trophoblast stem cells. Stem cell reports 5 40280139
2016 Ex vivo culture of pre-placental tissues reveals that the allantois is required for maintained expression of Gcm1 and Tpbpα. Placenta 4 27780534
2020 Correction: SP1-activated long noncoding RNA lncRNA GCMA functions as a competing endogenous RNA to promote tumor metastasis by sponging miR-124 and miR-34a in gastric cancer. Oncogene 3 32913198
2012 PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation. Biomedical research (Tokyo, Japan) 3 22975632
2024 Hypoxia and loss of GCM1 expression prevents differentiation and contact inhibition in human trophoblast stem cells. bioRxiv : the preprint server for biology 2 39314437
2025 Functional Interaction of GCM1 and LINC01118 Regulates Syncytiotrophoblast Differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41117589
2025 Gcm1 Orchestrates Lef1 Expression in Folate Deficiency-Induced Neural Tube Defects. Molecular neurobiology 0 41217685
2025 Evolution and expression of glial cells missing (GCM1 and GCM2) in monotremes suggest an ancient role in reproduction. Open biology 0 41537828