Affinage

GMEB1

Glucocorticoid modulatory element-binding protein 1 · UniProt Q9Y692

Length
573 aa
Mass
62.6 kDa
Annotated
2026-04-28
28 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GMEB1 is a SAND-domain transcription factor and cytoplasmic anti-apoptotic regulator that integrates glucocorticoid signaling, gene-specific transcriptional activation, and caspase inhibition. Its SAND domain (KDWK motif) mediates sequence-specific DNA binding to the glucocorticoid modulatory element (GME), where GMEB1 forms a ~550 kDa heteromeric complex with GMEB2 and directly contacts the glucocorticoid receptor and coactivator CBP to shift agonist dose-response properties (PMID:7665613, PMID:10894151, PMID:12702733). Beyond glucocorticoid modulation, GMEB1 trans-activates dopaminergic genes (Th, Dat) in midbrain neurons—its knockdown causing severe motor deficits—and directly activates YAP1 transcription in hepatocellular carcinoma cells (PMID:31175277, PMID:37389116). In the cytoplasm, GMEB1 functions as an endogenous inhibitor of initiator procaspases (caspase-2, -8, -9) by binding their prodomains, and separately stabilizes CFLARL by recruiting the deubiquitinase USP40 to prevent K48-linked ubiquitination, thereby blocking DISC formation and TRAIL-induced apoptosis (PMID:16497673, PMID:31046799).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    Identifying what binds the GME established that GMEB1 and GMEB2 form a novel ~550 kDa heteromeric complex that modulates glucocorticoid receptor transactivation by shifting dose-response and partial agonist properties, defining GMEB1 as a new class of GR modulatory factor.

    Evidence Partial purification, gel shift, size exclusion chromatography, and peptide sequencing from nuclear extracts

    PMID:7665613

    Open questions at the time
    • Identity of other subunits in the ~550 kDa complex unknown
    • Physiological target genes of GME-mediated modulation not identified
  2. 1998 High

    Cloning GMEB2 and demonstrating its heterodimeric GME binding with GMEB1 revealed that the conserved KDWK (SAND) domain defines a new transcription factor family shared with Drosophila DEAF-1.

    Evidence Degenerate PCR/RACE cloning, in vitro translation, gel shift with antibody supershift

    PMID:9651376

    Open questions at the time
    • Structural basis of KDWK-mediated DNA recognition not yet resolved
    • Stoichiometry of heterodimer on DNA unknown
  3. 2000 High

    Demonstrating that GMEB1 possesses intrinsic transactivation activity and directly contacts both GR and the coactivator CBP resolved how GMEB1 could modulate transcription—through a bridging mechanism rather than simple DNA occupancy.

    Evidence Mammalian one-hybrid and two-hybrid assays, pull-down assays, HAT activity assays

    PMID:10894151

    Open questions at the time
    • Whether GMEB1-CBP interaction is required in vivo for GR modulation not tested
    • GMEB1 interaction with TIF2 confirmed only by yeast two-hybrid
  4. 2002 Medium

    Domain mapping separated GMEB1's GR modulation function (requiring DNA binding, GR binding, and CBP binding domains) from its intrinsic transactivation, showing these are mechanistically independent activities; concurrent discovery of Ubc9 interaction suggested SUMO pathway cross-talk.

    Evidence Deletion mutagenesis, mammalian two-hybrid, reporter assays, co-IP with Ubc9 and Ubc9 catalytic mutants

    PMID:11812797 PMID:11934901

    Open questions at the time
    • Whether GMEB1 itself is SUMOylated not determined
    • MuRF1-GMEB1 interaction shown only in vitro, physiological relevance in muscle unconfirmed
  5. 2003 High

    The 1.55 Å crystal structure of the GMEB1 SAND domain established that the KDWK motif on an exposed α-helix is the DNA-recognition element and identified a novel structural zinc-binding site that constrains domain architecture without contributing to DNA binding.

    Evidence X-ray crystallography, NMR spectroscopy, site-directed mutagenesis, DNA binding assays

    PMID:12702733

    Open questions at the time
    • Structure of the GMEB1-GMEB2 heterodimer on DNA not solved
    • No co-crystal with GME DNA available
  6. 2006 High

    Discovery that GMEB1 binds the prodomains (CARD/DED) of procaspases-2, -8, and -9 and inhibits their activation established a second, cytoplasmic function as an endogenous anti-apoptotic factor; transgenic overexpression in mouse brain reduced ischemic infarct size, providing in vivo validation.

    Evidence Co-IP, caspase activation assays, siRNA knockdown, transgenic mouse focal ischemia model

    PMID:15555560 PMID:16497673

    Open questions at the time
    • Structural basis of prodomain recognition unknown
    • Whether nuclear versus cytoplasmic pools of GMEB1 are regulated differentially not addressed
  7. 2011 Medium

    Placing GMEB1 downstream of IL-12/PI3K/Akt signaling in T cells revealed a physiological circuit whereby cytokine signaling upregulates GMEB1 to counteract glucocorticoid-induced apoptosis.

    Evidence siRNA knockdown in human T cells, flow cytometry apoptosis assay, PI3K/Akt pharmacological inhibition

    PMID:21840619

    Open questions at the time
    • Whether IL-12 induction of GMEB1 is transcriptional or post-translational not defined
    • Relevance beyond dexamethasone-induced T cell apoptosis untested
  8. 2019 High

    Two parallel advances revealed GMEB1's anti-apoptotic mechanism in cancer (stabilizing CFLARL via USP40 recruitment to block TRAIL/DISC-mediated apoptosis) and its role as a transcriptional activator of dopaminergic identity genes (Th, Dat), establishing GMEB1 as functionally bifurcated between cytoplasmic survival signaling and nuclear transcriptional programming.

    Evidence Co-IP, GST pull-down, shRNA knockdown with A549 xenograft model (CFLARL/USP40); virus-based nuclear capture, RNA-seq, liDNase-seq, in vivo lentiviral knockdown with behavioral phenotyping (dopamine neurons)

    PMID:31046799 PMID:31175277

    Open questions at the time
    • How GMEB1 partitions between nucleus and cytoplasm in dopamine neurons unknown
    • Whether USP40 recruitment mechanism is direct or scaffold-mediated not resolved
    • Genome-wide GMEB1 binding targets in dopamine neurons not mapped by ChIP-seq
  9. 2021 Medium

    Identification of circGlis3-mediated GMEB1 degradation via the E3 ligase MIB2 uncovered a post-translational regulatory axis controlling GMEB1 protein levels and downstream HSP27 phosphorylation in pancreatic beta cells.

    Evidence RNA pull-down, co-IP, gain/loss-of-function in beta cell lines and mouse/human islet models

    PMID:34751796

    Open questions at the time
    • Whether MIB2 ubiquitinates GMEB1 directly or requires circGlis3 as adaptor not mechanistically dissected
    • Specific ubiquitin chain type on GMEB1 not identified
  10. 2023 Medium

    ChIP-qPCR demonstration that GMEB1 directly binds and trans-activates the YAP1 promoter in hepatocellular carcinoma cells expanded its transcriptional target repertoire to include a key oncogenic effector.

    Evidence ChIP-qPCR, dual-luciferase reporter assay, siRNA/overexpression with proliferation and migration assays in HCC cells

    PMID:37389116

    Open questions at the time
    • Genome-wide GMEB1 occupancy in HCC cells not profiled
    • Whether YAP1 activation is SAND-domain-dependent not tested
    • In vivo HCC model validation lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: how GMEB1 partitions between nuclear transcription factor and cytoplasmic caspase inhibitor roles; the genome-wide binding landscape of GMEB1 across cell types; and the structural basis by which GMEB1 recognizes caspase prodomains.
  • No genome-wide ChIP-seq for GMEB1 published
  • No structure of GMEB1 bound to caspase prodomain
  • Regulated nuclear-cytoplasmic shuttling mechanism uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3
Partners
CFLARCREBBPFOXL2GMEB2HSPB1NR3C1TRAF3USP40
Complex memberships
GMEB1-GMEB2 heteromeric complex (~550 kDa)

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 GMEB1 and GMEB2 bind to the glucocorticoid modulatory element (GME) as a heteromeric macromolecular complex of ~550 kDa, distinct from CREB/CREM/ATF family members, and modulate glucocorticoid receptor transactivation by shifting the agonist dose-response curve and increasing partial agonist activity of antiglucocorticoids. Partial purification, gel shift assays, size exclusion chromatography, peptide sequencing The Journal of biological chemistry High 7665613
1998 GMEB2 (67 kDa) forms a heteromeric complex with GMEB1 when bound to GME DNA, and shares a conserved KDWK domain with Drosophila DEAF-1 and Suppressin, defining a new family of transcription factors. Cloning via degenerate PCR and RACE, in vitro transcription/translation, gel shift assays, antibody supershift The Journal of biological chemistry High 9651376
1999 Human GMEB1 (hGMEB1) was identified as an HSP27-interacting protein; co-immunoprecipitation confirmed in vivo interaction of HSP27 with hGMEB1, and in vitro translated hGMEB1 specifically bound GME oligonucleotides. Yeast two-hybrid screening with HSP27 as bait, co-immunoprecipitation, in vitro gel shift assay FEBS letters Medium 10386584
2000 GMEB1 and GMEB2 each possess intrinsic transactivation activity and directly interact with glucocorticoid receptor (GR) as shown by mammalian two-hybrid and pull-down assays; they also interact with the coactivator CBP but lack histone acetyltransferase (HAT) activity. Mammalian one-hybrid and two-hybrid assays, pull-down assays, HAT activity assay Molecular endocrinology (Baltimore, Md.) High 10894151
2000 Mouse GMEB1 was identified as an interactor of the nuclear receptor coactivator TIF2 activation domain 2 by yeast two-hybrid screening, and in vitro translated mGMEB1 bound GME oligonucleotides alone or as a heterodimer with rGMEB2. Yeast two-hybrid screening, in vitro gel shift assay, transient transfection reporter assay FEBS letters Medium 10692587
2000 The GME requires positioning within ~250 bp upstream of a tandem GRE driving a complex promoter for activity; GME activity operates via a pathway parallel to, not shared with, GRE-mediated fold induction, and the GME has intrinsic basal promoter activity in the absence of GREs. Transient transfection reporter assays with positional and sequence mutants Molecular and cellular endocrinology Medium 10854715
2002 GMEB1 structure/activity analysis revealed separate, non-overlapping domains for GR modulation versus intrinsic transactivation; GR modulation requires combined domains for DNA binding, GR binding, and CBP binding, while homo- and heterooligomerization domains were mapped. Deletion mutagenesis, mammalian two-hybrid assay, transient transfection reporter assay The Journal of biological chemistry Medium 11934901
2002 MURF-1 (MuRF1) binds GMEB1 in vitro, and endogenous MURF-1 is detected in nuclei of some myocytes, suggesting a link between titin/sarcomere signaling and GMEB1-mediated transcriptional regulation. In vitro binding assay, immunofluorescence localization of endogenous MURF-1 The Journal of cell biology Medium 11927605
2002 GMEB1 and GMEB2 interact with Ubc9 (the mammalian SUMO E2 enzyme), and Ubc9 also binds directly to glucocorticoid receptors; Ubc9 modulates GR transactivation properties (EC50, partial agonist activity) independently of its SUMO-transferase activity, and this activity requires only the GR ligand-binding domain and part of the hinge region. Co-immunoprecipitation, mammalian two-hybrid assay, transient transfection reporter assay with Ubc9 mutants The Journal of biological chemistry Medium 11812797
2003 Crystal structure (1.55 Å) of the GMEB1 SAND domain revealed that this domain is necessary and sufficient for GME DNA binding; NMR and mutagenesis mapped DNA recognition to an alpha-helical region exposing the conserved KDWK motif; the SAND domain also contains a novel zinc-binding motif that determines C-terminal conformation but is not required for DNA binding. X-ray crystallography, NMR spectroscopy, site-directed mutagenesis, DNA binding assays Molecular endocrinology (Baltimore, Md.) High 12702733
2004 GMEB1 binds to the prodomain (CARD) of procaspase-2 and inhibits its autoproteolytic activation by oligomerization, identifying GMEB1 as an endogenous inhibitor of procaspase-2 activation. Co-immunoprecipitation, in vitro binding assay, caspase activation assay Biochemical and biophysical research communications Medium 15555560
2004 GMEB2 structure/activity relationships closely parallel those of GMEB1: homo- and heterooligomerization, GR binding, CBP binding, DNA binding, and GR modulation all require large regions of the protein, while intrinsic transactivation localizes to a small domain; GR modulation of dose-response and partial agonist activity is independent of total GR-induced gene expression levels. Deletion mutagenesis, mammalian two-hybrid assay, transient transfection reporter assay Biochemistry Medium 14705952
2006 GMEB1 binds to procaspase-8 and procaspase-9 (in addition to procaspase-2), attenuates Fas-mediated caspase activation and apoptosis; siRNA knockdown of GMEB1 sensitizes cells to apoptotic stress; transgenic mice with neurospecific GMEB1 overexpression had smaller cerebral infarcts in transient focal ischemia. Co-immunoprecipitation, caspase activation assay, siRNA knockdown, transgenic mouse model with focal ischemia The Journal of biological chemistry High 16497673
2008 GMEB1 overexpression in human neuroblastoma SK-N-MC cells attenuates caspase activation and apoptosis induced by hypoxia and oxidative stress, extending its anti-apoptotic function beyond ischemia. Overexpression in cell culture, caspase activation assay, apoptosis assay Neuroscience letters Medium 18455874
2009 GMEB1 (as PIF p96) interacts with the N-terminal domain of RAG1 via a WW-like motif in RAG1; a luciferase reporter assay shows that a RAG1/GMEB1-containing complex can assemble in cells. Yeast two-hybrid assay, point mutagenesis of WW-like motif, luciferase reporter assay Nucleic acids research Low 19324890
2011 IL-12 induces GMEB1 expression in human T cells; siRNA knockdown of GMEB1 reverses the protective effect of IL-12 on dexamethasone-induced T cell apoptosis, placing GMEB1 downstream of IL-12/PI3K/Akt signaling in T cell survival. siRNA knockdown, flow cytometry apoptosis assay, pharmacological inhibition of PI3K/Akt Immunobiology Medium 21840619
2012 GMEB1 is a binding partner of the transcription factor FOXL2, identified by yeast two-hybrid and confirmed by co-immunoprecipitation; mutant FOXL2 proteins that aggregate in cells can sequester GMEB1 into aggregates; GMEB1 acts as a repressor on most FOXL2 target promoters but increases FOXL2 activity on the Per2 promoter, with differential effects on the oncogenic p.C134W mutant. Yeast two-hybrid screening, co-immunoprecipitation, fluorescence microscopy (aggregation), luciferase reporter assay Human molecular genetics Medium 22544055
2019 GMEB1 interacts with CFLARL (c-FLIPL) in the cytosol and promotes its stability by facilitating binding of the deubiquitinase USP40 to CFLARL, preventing K48-linked ubiquitination and degradation; this stabilization of CFLARL inhibits pro-caspase-8 activation, DISC formation upon TRAIL, and apoptosis in NSCLC cells; GMEB1 knockdown inhibited A549 xenograft tumor growth in vivo. Co-immunoprecipitation, GST pull-down, Western blotting, flow cytometry, immunofluorescence, shRNA knockdown, xenograft mouse model Journal of experimental & clinical cancer research : CR High 31046799
2019 Gmeb1 was identified as a transcriptional regulator of tyrosine hydroxylase (Th) and dopamine transporter (Dat) genes in midbrain dopamine neurons; Gmeb1 knockdown in dopamine neurons caused downregulation of Th and Dat and severe motor deficits in mice. Virus-based nuclear capture, RNA-seq, liDNase-seq (chromatin accessibility), predictive modeling, in vivo lentiviral knockdown with behavioral phenotyping Nature communications High 31175277
2020 TRAF3 directly interacts with GMEB1 (confirmed by co-immunoprecipitation in mammalian cells); overexpression of TRAF3 enhances GMEB1's anti-apoptotic function, while TRAF3 siRNA knockdown reduces it; RING and TRAF-C domains of TRAF3 are not required for this interaction. Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, cell viability assay Journal of biological research (Thessalonike, Greece) Medium 32514408
2021 CircGlis3 promotes GMEB1 degradation by facilitating interaction between GMEB1 and the E3 ubiquitin ligase MIB2, thereby suppressing phosphorylation of HSP27; this pathway mediates lipotoxicity-induced beta cell dysfunction and islet endothelial cell dysfunction. RNA pull-down, co-immunoprecipitation, gain/loss-of-function assays in cell lines and in vivo mouse and human models Diabetologia Medium 34751796
2023 GMEB1 binds to the YAP1 promoter region and positively regulates YAP1 transcription in hepatocellular carcinoma cells; validated by dual-luciferase reporter assay and ChIP-qPCR; GMEB1 overexpression promoted HCC cell proliferation, migration, and invasion while suppressing apoptosis. Dual-luciferase reporter assay, chromatin immunoprecipitation-qPCR, siRNA/overexpression with cell proliferation/migration/apoptosis assays World journal of gastrointestinal oncology Medium 37389116

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1. The Journal of cell biology 200 11927605
2002 Ubc9 is a novel modulator of the induction properties of glucocorticoid receptors. The Journal of biological chemistry 78 11812797
1995 The factor binding to the glucocorticoid modulatory element of the tyrosine aminotransferase gene is a novel and ubiquitous heteromeric complex. The Journal of biological chemistry 47 7665613
2000 Properties of the glucocorticoid modulatory element binding proteins GMEB-1 and -2: potential new modifiers of glucocorticoid receptor transactivation and members of the family of KDWK proteins. Molecular endocrinology (Baltimore, Md.) 44 10894151
2012 Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles. Human molecular genetics 41 22544055
2003 Crystal structure and nuclear magnetic resonance analyses of the SAND domain from glucocorticoid modulatory element binding protein-1 reveals deoxyribonucleic acid and zinc binding regions. Molecular endocrinology (Baltimore, Md.) 39 12702733
1998 Cloning and characterization of a novel binding factor (GMEB-2) of the glucocorticoid modulatory element. The Journal of biological chemistry 34 9651376
2000 Ability of the glucocorticoid modulatory element to modify glucocorticoid receptor transactivation indicates parallel pathways for the expression of glucocorticoid modulatory element and glucocorticoid response element activities. Molecular and cellular endocrinology 27 10854715
2019 Glucocorticoid modulatory element-binding protein 1 (GMEB1) interacts with the de-ubiquitinase USP40 to stabilize CFLARL and inhibit apoptosis in human non-small cell lung cancer cells. Journal of experimental & clinical cancer research : CR 26 31046799
2021 Lipotoxicity-induced circGlis3 impairs beta cell function and is transmitted by exosomes to promote islet endothelial cell dysfunction. Diabetologia 25 34751796
2006 Glucocorticoid modulatory element-binding protein 1 binds to initiator procaspases and inhibits ischemia-induced apoptosis and neuronal injury. The Journal of biological chemistry 25 16497673
2022 Fatty acid metabolism-related genes are associated with flavor-presenting aldehydes in Chinese local chicken. Frontiers in genetics 22 36035160
1999 Cloning and characterization of hGMEB1, a novel glucocorticoid modulatory element binding protein. FEBS letters 22 10386584
2000 Genomic organization of human GMEB-1 and rat GMEB-2: structural conservation of two multifunctional proteins. Nucleic acids research 18 10734202
2011 IL-12 inhibits glucocorticoid-induced T cell apoptosis by inducing GMEB1 and activating PI3K/Akt pathway. Immunobiology 17 21840619
2002 Structure/activity elements of the multifunctional protein, GMEB-1. Characterization of domains relevant for the modulation of glucocorticoid receptor transactivation properties. The Journal of biological chemistry 17 11934901
2000 Cloning of a mouse glucocorticoid modulatory element binding protein, a new member of the KDWK family. FEBS letters 15 10692587
2008 GMEB1, a novel endogenous caspase inhibitor, prevents hypoxia- and oxidative stress-induced neuronal apoptosis. Neuroscience letters 14 18455874
2004 Regulation of procaspase-2 by glucocorticoid modulatory element-binding protein 1 through the interaction with caspase recruitment domain. Biochemical and biophysical research communications 12 15555560
2009 A WW-like module in the RAG1 N-terminal domain contributes to previously unidentified protein-protein interactions. Nucleic acids research 10 19324890
2020 TRAF3 can interact with GMEB1 and modulate its anti-apoptotic function. Journal of biological research (Thessalonike, Greece) 9 32514408
2019 In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function. Nature communications 8 31175277
2004 Structure/activity relationships for GMEB-2: the second member of the glucocorticoid modulatory element-binding complex. Biochemistry 7 14705952
2023 Withdrawn: Z. Cui, Q. Sun, W. Yan, Q. Han, G. Wang, Y. Hu. The role of miR-320a and its target gene GMEB1 in epithelial-mesenchymal transition and invasion of colorectal cancer, published in The Journal of Gene Medicine. The journal of gene medicine 6 33617082
2023 Chromatin Accessibility and Transcriptional Landscape during Inhibition of Salmonella enterica by Lactobacillus reuteri in IPEC-J2 Cells. Cells 5 36980306
2022 Identification of functionally important miRNA targeted genes associated with child obesity trait in genome-wide association studies. BMC genomics 4 35546387
2023 Transcription factor glucocorticoid modulatory element-binding protein 1 promotes hepatocellular carcinoma progression by activating Yes-associate protein 1. World journal of gastrointestinal oncology 2 37389116
2018 From Matrices to Knowledge: Using Semantic Networks to Annotate the Connectome. Frontiers in neuroanatomy 2 30581382