Affinage

GRHL1

Grainyhead-like protein 1 homolog · UniProt Q9NZI5

Length
618 aa
Mass
70.1 kDa
Annotated
2026-06-10
39 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRHL1 (LBP-32/MGR) is a sequence-specific DNA-binding transcription factor that localizes to the nucleus and regulates programs of epithelial integrity, proliferation, and cell adhesion (PMID:16730372, PMID:33931584). Its DNA-binding domain engages target promoters both at canonical sites and at non-canonical sequences lacking the previously obligatory CNNG core motif, as confirmed by direct calorimetric binding measurements (PMID:38049725). GRHL1 activity is gated by signal-dependent nuclear translocation: EGF stimulation drives phosphorylation at Ser76 through the EGFR-ERK axis, promoting nuclear accumulation and transcriptional activation of cell cycle genes (PMID:33931584). At individual promoters its output is context-specific — it represses the human P450scc promoter (PMID:16730372) while activating Cyclin D1 (CCND1) and other proliferation genes (PMID:33931584, PMID:42207451). Through direct regulation of Desmoglein 1 (DSG1), GRHL1 controls desmosome formation required for inner ear epithelial integrity, and its loss in zebrafish causes otolith, hair cell, and hearing defects rescuable by DSG1 (PMID:25896282). In neuroblastoma, GRHL1 functions as a tumor suppressor whose transcription is silenced by an HDAC3/MYCN complex at its promoter, and whose enforced expression suppresses anchorage-independent growth, proliferation, and xenograft tumor growth (PMID:24419085). Its own promoter is positively cross-regulated by related LBP family factors LBP-1b and LBP-9 (PMID:18004979).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 Medium

    Established GRHL1 as a nuclear, sequence-specific DNA-binding protein with transcriptional repressor activity, defining it as a functional transcription factor.

    Evidence In vitro DNA binding to the P450scc promoter, nuclear localization in transfected cells, and luciferase reporter repression

    PMID:16730372

    Open questions at the time
    • Endogenous occupancy of the P450scc promoter not demonstrated
    • Mechanism of repression (cofactors) not identified
    • Limited to a single target promoter in vitro
  2. 2008 Medium

    Mapped the GRHL1 core promoter and showed its expression is restricted to syncytiotrophoblasts and cross-regulated by related LBP transcription factors, addressing how GRHL1 itself is controlled.

    Evidence RT-PCR from isolated placental cells, primer extension to map transcription start, and promoter-luciferase co-transfection with LBP-1b and LBP-9

    PMID:18004979

    Open questions at the time
    • Direct binding of LBP-1b/LBP-9 to the GRHL1 promoter not shown
    • Functional consequence of cross-regulation in vivo unknown
  3. 2014 High

    Defined GRHL1 as a tumor suppressor whose silencing by an HDAC3/MYCN complex links its loss to neuroblastoma, and identified a genome-wide target program in development, proliferation, and adhesion.

    Evidence ChIP for HDAC3/MYCN and histone acetylation, genome-wide expression profiling, gain/loss-of-function in cell lines, and xenograft assays

    PMID:24419085

    Open questions at the time
    • Direct GRHL1 target genes mediating tumor suppression not pinpointed
    • Whether MYCN repression of GRHL1 occurs in patient tumors not established
  4. 2015 High

    Placed GRHL1 in a desmosome-formation pathway by showing inner ear malformations from Grhl1 loss are rescued by its target DSG1, establishing a developmental and epithelial-integrity role.

    Evidence Morpholino knockdown in zebrafish, rescue with GRHL1 and DSG1, electron microscopy of desmosomes, and hair cell apoptosis assay

    PMID:25896282

    Open questions at the time
    • Direct GRHL1 binding to the DSG1 promoter not shown in this study
    • Conservation of this axis in mammalian inner ear not addressed
  5. 2021 High

    Revealed the activating mechanism by which extracellular signaling controls GRHL1: EGFR-ERK phosphorylation at Ser76 drives nuclear translocation to activate cell cycle gene transcription in lung cancer.

    Evidence RNA-seq after knockdown, ChIP for promoter binding, Ser76 site-directed mutagenesis, nuclear translocation and EGF stimulation assays

    PMID:33931584

    Open questions at the time
    • Kinase directly phosphorylating Ser76 not biochemically identified
    • Reconciliation with tumor-suppressor role in neuroblastoma not addressed
  6. 2023 Medium

    Redefined GRHL1 DNA-binding specificity by demonstrating direct binding to non-canonical sites lacking the CNNG core motif, broadening its potential target repertoire.

    Evidence Deep-learning model trained on HT-SELEX and ChIP-Seq, with isothermal titration calorimetry and mutagenesis on the GRHL1 DNA-binding domain

    PMID:38049725

    Open questions at the time
    • Functional regulation of genes via non-canonical sites in cells not shown
    • Single lab, not independently replicated
  7. 2026 Medium

    Connected an upstream RNA-protein complex to GRHL1 activation, showing an ACPH/tsRNA-Gly complex drives GRHL1 nuclear translocation and CCND1 induction during liver regeneration.

    Evidence tsRNA-Gly overexpression/knockdown, Co-IP of the ACPH-tsRNA-Gly complex, nuclear translocation assay, ChIP for CCND1 promoter, and liver regeneration assays

    PMID:42207451

    Open questions at the time
    • Mechanism linking ACPH/tsRNA-Gly to GRHL1 translocation not resolved
    • Single lab, not independently replicated
    • Relationship to EGFR-ERK/Ser76 pathway unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRHL1's opposing repressive versus activating outputs and its tumor-suppressor versus proliferation-promoting roles are reconciled at the level of cofactor recruitment and promoter context remains unresolved.
  • No structural or cofactor-level basis for context-dependent activation versus repression
  • Direct transcriptional cofactors of GRHL1 not identified
  • Relationship among the EGFR-ERK, HDAC3/MYCN, and ACPH/tsRNA-Gly inputs not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1266738 Developmental Biology 1
Partners
CCND1DSG1HDAC3MYCN

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 LBP-32/MGR (GRHL1) protein binds preferentially to a DNA fragment from the P450scc promoter in vitro and exhibits nuclear localization in transfected cells; it specifically represses transcriptional activation of the human P450scc promoter as shown by luciferase reporter gene assays. In vitro DNA binding assay, transfection with nuclear localization observation, luciferase reporter gene assay Placenta Medium 16730372
2008 LBP-32/MGR (GRHL1) mRNA is expressed specifically in syncytiotrophoblasts (not cytotrophoblasts) of human placenta. LBP-1b and LBP-9 co-transfected with the LBP-32/MGR promoter both stimulated LBP-32/MGR promoter activity, indicating transcriptional cross-regulation among these LBP transcription factors. A core promoter region from -639 to -184 bp was identified. RT-PCR from isolated cell populations, primer extension assay to identify transcription start site, promoter-luciferase reporter co-transfection assay DNA and cell biology Medium 18004979
2014 GRHL1 acts as a tumor suppressor in neuroblastoma. HDAC3 and MYCN colocalize to the GRHL1 promoter and repress its transcription; HDAC inhibitor treatment increases histone H4 pan-acetylation at the GRHL1 promoter preceding transcriptional activation. Enforced GRHL1 expression inhibited anchorage-independent colony formation and proliferation, and retarded xenograft growth; GRHL1 knockdown promoted colony formation. GRHL1 regulated 170 genes genome-wide involved in nervous system development, proliferation, and cell adhesion pathways. ChIP (HDAC3 and MYCN co-localization at promoter), histone acetylation ChIP, genome-wide expression screen, gain-of-function/loss-of-function in cell lines, xenograft mouse model Cancer research High 24419085
2015 Grhl1 deficiency in zebrafish causes inner ear developmental malformations (missing otoliths, disordered hair cells, deafness). These defects were partially rescued by GRHL1 or its target gene DSG1 (Desmoglein 1), indicating GRHL1 acts via regulation of desmosome junction formation in inner ear epithelia. Electron microscopy confirmed damaged desmosomes in otic sensory epithelium of grhl1 morphants. Morpholino knockdown in zebrafish, rescue experiments with GRHL1 and DSG1, electron microscopy, hair cell apoptosis assay The International journal of developmental biology High 25896282
2021 GRHL1 promotes cell cycle progression in lung cancer cells by binding to promoter regions of cell cycle-related genes and increasing their transcription. EGF stimulation activates GRHL1 and promotes its nuclear translocation via phosphorylation at Ser76 mediated by the EGFR-ERK axis. RNA sequencing after GRHL1 knockdown, ChIP (GRHL1 binding to promoters), nuclear translocation assay, site-directed mutagenesis of Ser76, EGF stimulation assays, knockdown/overexpression proliferation assays Cell death & disease High 33931584
2023 GRHL1 can bind non-canonical DNA sequences lacking the previously considered obligatory CNNG core motif. Isothermal titration calorimetry experimentally confirmed binding between the GRHL1 DNA-binding domain and predicted non-canonical binding sites. Mutagenesis of individual nucleotides showed a correlation between predicted binding strength and experimentally validated binding affinity. Deep learning (convolutional recurrent neural network) trained on HT-SELEX data, ChIP-Seq, isothermal titration calorimetry (ITC) with GRHL1 DNA-binding domain, mutagenesis of binding sequences BMC genomics Medium 38049725
2026 GRHL1 is activated downstream of the ACPH/tsRNA-Gly complex: stabilized ACPH forms a functional complex with tsRNA-Gly that drives GRHL1 nuclear translocation and transcriptional upregulation of Cyclin D1 (CCND1) via direct promoter binding, facilitating liver cell regeneration. Overexpression and knockdown of tsRNA-Gly, co-immunoprecipitation (ACPH-tsRNA-Gly complex), nuclear translocation assay, ChIP (GRHL1 binding to CCND1 promoter), functional liver regeneration assays Science China. Life sciences Medium 42207451

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mgr, a novel global regulator in Staphylococcus aureus. Journal of bacteriology 133 12813062
2006 Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment. Circulation 78 17030689
1988 Functional monopolar spindles caused by mutation in mgr, a cell division gene of Drosophila melanogaster. Journal of cell science 61 3138251
2014 GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3. Cancer research 47 24419085
1990 Differential expression of laminin chains and receptor (LBP-32) in fetal and neoplastic hepatocytes compared to normal adult hepatocytes in vivo and in culture. The American journal of pathology 44 2144711
2013 The fibrillin-1 hypomorphic mgR/mgR murine model of Marfan syndrome shows severe elastolysis in all segments of the aorta. Journal of vascular surgery 37 23294503
1998 Interactions between mgr, asp, and polo: asp function modulated by polo and needed to maintain the poles of monopolar and bipolar spindles. Chromosoma 27 9914377
2012 Drosophila Mgr, a Prefoldin subunit cooperating with von Hippel Lindau to regulate tubulin stability. Proceedings of the National Academy of Sciences of the United States of America 26 22451918
1996 Synthesis and Characterization of Six-Coordinate Nitrido Complexes of Vanadium(V), Chromium(V), and Manganese(V). Isolation of a Dinuclear, Mixed-Valent &mgr;-Nitrido Chromium(III)/Chromium(V) Species. Inorganic chemistry 19 11666264
1996 Metal Binding of Polyalcohols. 4. Structure and Magnetism of the Hexanuclear, &mgr;(6)-Oxo-Centered [OFe(6)(H(-)(3)thme)(3)(OCH(3))(3)Cl(6)](2)(-) (thme = 1,1,1-Tris(hydroxymethyl)ethane). Inorganic chemistry 18 11666660
1991 Expression of laminin and its receptor LBP-32 in human and rat hepatoma cells. Hepatology (Baltimore, Md.) 18 1847349
2021 EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer. Cell death & disease 14 33931584
2008 LBP-1b, LBP-9, and LBP-32/MGR detected in syncytiotrophoblasts from first-trimester human placental tissue and their transcriptional regulation. DNA and cell biology 13 18004979
2016 Loss of Endothelial Barrier in Marfan Mice (mgR/mgR) Results in Severe Inflammation after Adenoviral Gene Therapy. PloS one 12 26840980
1997 (&mgr;-Oxo)bis(&mgr;-carboxylato)bis(2,2'-bipyridyl)bis(X)diiron(III) Complexes, X = NCS(-), NCSe(-), and N(3)(-): Synthetic Models of Pseudohalide Derivatives of Carboxylate-Bridged Diiron Proteins. Inorganic chemistry 12 11670117
2006 Human LBP-32/MGR is a repressor of the P450scc in human choriocarcinoma cell line JEG-3. Placenta 11 16730372
1984 Benzyl derivative facilitation of transcription in Escherichia coli at the ara and lac operon promoters: metabolite gene regulation (MGR). Molecular & general genetics : MGG 11 6319971
1993 Interferons upregulate the expression of laminin and its receptor LBP-32 in cultured cells. Journal of biological regulators and homeostatic agents 9 7688491
2015 Grhl1 deficiency affects inner ear development in zebrafish. The International journal of developmental biology 8 25896282
2013 High-sensitivity immunofluorescence staining: a comparison of the liposome procedure and the FASER technique on mGR detection. Journal of fluorescence 8 23408089
2001 Diode-Laser Spectroscopy: Line Profiles of H(2)O in the Region of 1.39 &mgr;m. Journal of molecular spectroscopy 8 11437549
1996 Molecular Assemblies Containing Unsupported [Fe(III)-(&mgr;(2):eta(2)-RCO(2))-Cu(II)] Bridges. Inorganic chemistry 7 11666470
1998 A New Class of Complexes Possessing Cofacially-Oriented, Planar, Metal-Containing Subunits. Synthesis, Characterization, and Reactivity of [(MoO(2))(2)(&mgr;-O)](2+)-Linked, Catechol-Functionalized, Tetraazamacrocyclic and Salicylideneamine Complexes. Inorganic chemistry 6 11670322
1997 Synthesis of a &mgr;,eta(2)-Disulfide-Bridged Hexanuclear Ru(II)-Na Cluster Formed from the Reductive Coupling of a &mgr;,eta(1)-Disulfide-Bridged Dinuclear Ru(III) Complex. Inorganic chemistry 6 11670099
1992 The metabotropic glutamate receptor (MGR): pharmacology and subcellular location. Journal of physiology, Paris 6 1343596
1996 Synthesis, Spectroscopic Characterization, and Structural Studies of Bis(&mgr;-sulfido)bis[{O,O-dialkyl (alkylene) dithiophosphato}oxomolybdenum(V)] Complexes. Crystal Structures of Mo(2)O(2)S(2)[S(2)P(OEt)(2)](2), Mo(2)O(2)S(2)[S(2)P(OEt)(2)](2).2NC(5)H(5), and Mo(2)O(3)[S(2)P(OPh)(2)](4). Inorganic chemistry 5 11666485
1996 Preparation, Molecular and Electronic Structures, and Magnetic Properties of Face-Sharing Bioctahedral Titanium(III) Compounds: [PPh(4)][Ti(2)(&mgr;-Cl)(3)Cl(4)(PR(3))(2)]. Inorganic chemistry 5 11666929
2024 Exploration of the Correlation Between GRHL1 Expression and Tumor Microenvironment in Endometrial Cancer and Immunotherapy. Pharmacogenomics and personalized medicine 4 38586176
1999 Experimental and Theoretical Investigation of the Molecular and Electronic Structure of [Zn(4)(&mgr;(4)-S){&mgr;-S(2)As(CH(3))(2)}(6)] and [Cd(4)(&mgr;(4)-S){&mgr;-S(2)As(CH(3))(2)}(6)]: Two Possible Molecular Models of Extended Metal Chalcogenide Semiconductors. Inorganic chemistry 4 11670896
1997 Structural and Spectroscopic Studies of Two Phases of the Organometallic Chain Polymer [Ru(2){&mgr;(2):&mgr;(2):eta(2)-O(2)PMe(2)}(2)(CO)(4)](n)(). Inorganic chemistry 4 11670201
1992 Cell-specific expression of LBP-32 mRNA in retina and other locations of newborn mouse eye as revealed by in situ hybridization. Current eye research 3 1424732
2025 Stabilisation of extracellular matrix is crucial to rapamycin-mediated life span increase in Marfan mgR/mgR mice. Biochemical pharmacology 2 40021021
1997 Copper(I)-Purine-Phosphine Complexes. Syntheses and Molecular Structures of [Cu(2)(&mgr;-HL(1))(2)(&mgr;-dppm)(eta(1)-dppm)(2)] and {[Cu(3)(&mgr;(3)-Cl)(2)(&mgr;-dppm)(3)][Cu(HL(2))(2)]} (H(2)L(1) = 8-Mercaptotheophylline and H(2)L(2) = 8-Ethyl-3-methylxanthine). Inorganic chemistry 2 11669672
1996 Isolation of a Bismuth Chloride-Iron Carbonyl Adduct: Synthesis and Structural Characterization of [PhCH(2)NMe(3)](2)[Bi(2)Cl(4)(&mgr;-Cl)(2){&mgr;-Fe(CO)(4)}]. Inorganic chemistry 2 11666658
2023 Discovery of a non-canonical GRHL1 binding site using deep convolutional and recurrent neural networks. BMC genomics 1 38049725
1999 Microporous Montmorillonites Expanded with Alumina Clusters and M[(&mgr;-OH)Cu(&mgr;-OCH(2)CH(2)NEt(2))](6)(ClO(4))(3), (M = Al, Ga, and Fe), or Cr[(&mgr;-OCH(3))(&mgr;-OCH(2)CH(2)NEt(2))CuCl](3) Complexes. Inorganic chemistry 1 11670992
2026 Transfer RNA-derived small RNA-Gly activates the ACPH/GRHL1 axis to facilitate liver cell regeneration in acute-on chronic liver failure. Science China. Life sciences 0 42207451
2001 Preparation of anfi-CD3 and anti-IgM&mgr; chain bispecific antibody by cell fusion. Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA 0 12426160
1999 Human &mgr; Opioid Receptor Expressed in Sf9 Insect Cells was Functionally Coupled to Endogenous G Protein. Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica 0 12114979

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