{"gene":"GRHL1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2006,"finding":"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.","method":"In vitro DNA binding assay, transfection with nuclear localization observation, luciferase reporter gene assay","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus reporter assay plus nuclear localization, single lab, multiple orthogonal methods","pmids":["16730372"],"is_preprint":false},{"year":2008,"finding":"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.","method":"RT-PCR from isolated cell populations, primer extension assay to identify transcription start site, promoter-luciferase reporter co-transfection assay","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter mapping with reporter assay and co-transfection, single lab, multiple orthogonal methods","pmids":["18004979"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, functional gain/loss-of-function with multiple phenotypic readouts, in vivo xenograft, multiple orthogonal methods in one study","pmids":["24419085"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Morpholino knockdown in zebrafish, rescue experiments with GRHL1 and DSG1, electron microscopy, hair cell apoptosis assay","journal":"The International journal of developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific phenotypic readout, pathway placement via rescue with target gene DSG1, ultrastructural validation, multiple orthogonal methods","pmids":["25896282"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, mutagenesis of phosphorylation site, nuclear translocation, RNA-seq, multiple orthogonal methods in one study, single lab","pmids":["33931584"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ITC with mutagenesis confirms binding, but single lab and novel finding not yet replicated","pmids":["38049725"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, ChIP, nuclear translocation assay, functional readout; single lab, findings not yet independently replicated","pmids":["42207451"],"is_preprint":false}],"current_model":"GRHL1 (also known as LBP-32/MGR/TFCP2L2) is a transcription factor that binds DNA via a defined binding domain (including non-canonical sites lacking the CNNG core motif) and localizes to the nucleus upon activation; it is phosphorylated at Ser76 by the EGFR-ERK axis to promote nuclear translocation, where it directly binds promoters to regulate target genes including P450scc (repression), cell cycle genes (activation via CCND1), and DSG1 (desmosome formation); its transcription is repressed by an HDAC3/MYCN complex at its promoter, and it acts as a tumor suppressor in neuroblastoma while playing essential roles in inner ear epithelial integrity via desmosome regulation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2006,"claim":"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","pmids":["16730372"],"confidence":"Medium","gaps":["Endogenous occupancy of the P450scc promoter not demonstrated","Mechanism of repression (cofactors) not identified","Limited to a single target promoter in vitro"]},{"year":2008,"claim":"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","pmids":["18004979"],"confidence":"Medium","gaps":["Direct binding of LBP-1b/LBP-9 to the GRHL1 promoter not shown","Functional consequence of cross-regulation in vivo unknown"]},{"year":2014,"claim":"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","pmids":["24419085"],"confidence":"High","gaps":["Direct GRHL1 target genes mediating tumor suppression not pinpointed","Whether MYCN repression of GRHL1 occurs in patient tumors not established"]},{"year":2015,"claim":"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","pmids":["25896282"],"confidence":"High","gaps":["Direct GRHL1 binding to the DSG1 promoter not shown in this study","Conservation of this axis in mammalian inner ear not addressed"]},{"year":2021,"claim":"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","pmids":["33931584"],"confidence":"High","gaps":["Kinase directly phosphorylating Ser76 not biochemically identified","Reconciliation with tumor-suppressor role in neuroblastoma not addressed"]},{"year":2023,"claim":"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","pmids":["38049725"],"confidence":"Medium","gaps":["Functional regulation of genes via non-canonical sites in cells not shown","Single lab, not independently replicated"]},{"year":2026,"claim":"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","pmids":["42207451"],"confidence":"Medium","gaps":["Mechanism linking ACPH/tsRNA-Gly to GRHL1 translocation not resolved","Single lab, not independently replicated","Relationship to EGFR-ERK/Ser76 pathway unclear"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,4,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,6]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3]}],"complexes":[],"partners":["DSG1","CCND1","MYCN","HDAC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZI5","full_name":"Grainyhead-like protein 1 homolog","aliases":["Mammalian grainyhead","NH32","Transcription factor CP2-like 2","Transcription factor LBP-32"],"length_aa":618,"mass_kda":70.1,"function":"Transcription factor involved in epithelial development. Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' (PubMed:12175488, PubMed:18288204, PubMed:29309642). Important regulator of DSG1 in the context of hair anchorage and epidermal differentiation, participates in the maintenance of the skin barrier. There is no genetic interaction with GRHL3, nor functional cooperativity due to diverse target gene selectivity during epithelia development (By similarity). May play a role in regulating glucose homeostasis and insulin signaling Functions as a transcription activator May function as a repressor in tissues where both isoform 1 and isoform 2 are expressed","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NZI5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRHL1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRHL1","total_profiled":1310},"omim":[{"mim_id":"620222","title":"SPERMATOGENIC FAILURE 80; SPGF80","url":"https://www.omim.org/entry/620222"},{"mim_id":"615294","title":"CILIARY DYSKINESIA, PRIMARY, 21; CILD21","url":"https://www.omim.org/entry/615294"},{"mim_id":"615288","title":"DYNEIN REGULATORY COMPLEX, SUBUNIT 1; DRC1","url":"https://www.omim.org/entry/615288"},{"mim_id":"609786","title":"GRAINYHEAD-LIKE 1; GRHL1","url":"https://www.omim.org/entry/609786"},{"mim_id":"608576","title":"GRAINYHEAD-LIKE 2; GRHL2","url":"https://www.omim.org/entry/608576"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":114.7},{"tissue":"skin 1","ntpm":84.6},{"tissue":"vagina","ntpm":65.5}],"url":"https://www.proteinatlas.org/search/GRHL1"},"hgnc":{"alias_symbol":["LBP-32","MGR"],"prev_symbol":["TFCP2L2"]},"alphafold":{"accession":"Q9NZI5","domains":[{"cath_id":"-","chopping":"28-56","consensus_level":"medium","plddt":88.3972,"start":28,"end":56},{"cath_id":"2.60.40","chopping":"253-289_298-437_457-463","consensus_level":"high","plddt":92.1344,"start":253,"end":463},{"cath_id":"3.10.20","chopping":"532-618","consensus_level":"high","plddt":93.2551,"start":532,"end":618}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZI5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZI5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZI5-F1-predicted_aligned_error_v6.png","plddt_mean":67.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRHL1","jax_strain_url":"https://www.jax.org/strain/search?query=GRHL1"},"sequence":{"accession":"Q9NZI5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZI5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZI5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZI5"}},"corpus_meta":[{"pmid":"12813062","id":"PMC_12813062","title":"Mgr, a novel global regulator in Staphylococcus aureus.","date":"2003","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/12813062","citation_count":133,"is_preprint":false},{"pmid":"17030689","id":"PMC_17030689","title":"Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment.","date":"2006","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/17030689","citation_count":78,"is_preprint":false},{"pmid":"3138251","id":"PMC_3138251","title":"Functional monopolar spindles caused by mutation in mgr, a cell division gene of Drosophila melanogaster.","date":"1988","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/3138251","citation_count":61,"is_preprint":false},{"pmid":"24419085","id":"PMC_24419085","title":"GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24419085","citation_count":47,"is_preprint":false},{"pmid":"2144711","id":"PMC_2144711","title":"Differential expression of laminin chains and receptor (LBP-32) in fetal and neoplastic hepatocytes compared to normal adult hepatocytes in vivo and in culture.","date":"1990","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2144711","citation_count":44,"is_preprint":false},{"pmid":"23294503","id":"PMC_23294503","title":"The fibrillin-1 hypomorphic mgR/mgR murine model of Marfan syndrome shows severe elastolysis in all segments of the aorta.","date":"2013","source":"Journal of vascular surgery","url":"https://pubmed.ncbi.nlm.nih.gov/23294503","citation_count":37,"is_preprint":false},{"pmid":"9914377","id":"PMC_9914377","title":"Interactions between mgr, asp, and polo: asp function modulated by polo and needed to maintain the poles of monopolar and bipolar spindles.","date":"1998","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/9914377","citation_count":27,"is_preprint":false},{"pmid":"22451918","id":"PMC_22451918","title":"Drosophila Mgr, a Prefoldin subunit cooperating with von Hippel Lindau to regulate tubulin stability.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22451918","citation_count":26,"is_preprint":false},{"pmid":"11666264","id":"PMC_11666264","title":"Synthesis and Characterization of Six-Coordinate Nitrido Complexes of Vanadium(V), Chromium(V), and Manganese(V). 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Synthesis, Characterization, and Reactivity of [(MoO(2))(2)(&mgr;-O)](2+)-Linked, Catechol-Functionalized, Tetraazamacrocyclic and Salicylideneamine Complexes.","date":"1998","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11670322","citation_count":6,"is_preprint":false},{"pmid":"11670099","id":"PMC_11670099","title":"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.","date":"1997","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11670099","citation_count":6,"is_preprint":false},{"pmid":"11666485","id":"PMC_11666485","title":"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).","date":"1996","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11666485","citation_count":5,"is_preprint":false},{"pmid":"11666929","id":"PMC_11666929","title":"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)].","date":"1996","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11666929","citation_count":5,"is_preprint":false},{"pmid":"38586176","id":"PMC_38586176","title":"Exploration of the Correlation Between GRHL1 Expression and Tumor Microenvironment in Endometrial Cancer and Immunotherapy.","date":"2024","source":"Pharmacogenomics and personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38586176","citation_count":4,"is_preprint":false},{"pmid":"11670201","id":"PMC_11670201","title":"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)().","date":"1997","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11670201","citation_count":4,"is_preprint":false},{"pmid":"11670896","id":"PMC_11670896","title":"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.","date":"1999","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11670896","citation_count":4,"is_preprint":false},{"pmid":"1424732","id":"PMC_1424732","title":"Cell-specific expression of LBP-32 mRNA in retina and other locations of newborn mouse eye as revealed by in situ hybridization.","date":"1992","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/1424732","citation_count":3,"is_preprint":false},{"pmid":"40021021","id":"PMC_40021021","title":"Stabilisation of extracellular matrix is crucial to rapamycin-mediated life span increase in Marfan mgR/mgR mice.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40021021","citation_count":2,"is_preprint":false},{"pmid":"11669672","id":"PMC_11669672","title":"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).","date":"1997","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11669672","citation_count":2,"is_preprint":false},{"pmid":"11666658","id":"PMC_11666658","title":"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)}].","date":"1996","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11666658","citation_count":2,"is_preprint":false},{"pmid":"38049725","id":"PMC_38049725","title":"Discovery of a non-canonical GRHL1 binding site using deep convolutional and recurrent neural networks.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38049725","citation_count":1,"is_preprint":false},{"pmid":"11670992","id":"PMC_11670992","title":"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.","date":"1999","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11670992","citation_count":1,"is_preprint":false},{"pmid":"42207451","id":"PMC_42207451","title":"Transfer RNA-derived small RNA-Gly activates the ACPH/GRHL1 axis to facilitate liver cell regeneration in acute-on chronic liver failure.","date":"2026","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42207451","citation_count":0,"is_preprint":false},{"pmid":"12426160","id":"PMC_12426160","title":"Preparation of anfi-CD3 and anti-IgM&mgr; chain bispecific antibody by cell fusion.","date":"2001","source":"Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA","url":"https://pubmed.ncbi.nlm.nih.gov/12426160","citation_count":0,"is_preprint":false},{"pmid":"12114979","id":"PMC_12114979","title":"Human &mgr; Opioid Receptor Expressed in Sf9 Insect Cells was Functionally Coupled to Endogenous G Protein.","date":"1999","source":"Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12114979","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25685,"output_tokens":2022,"usd":0.053692,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8995,"output_tokens":2889,"usd":0.0586,"stage2_stop_reason":"end_turn"},"total_usd":0.112292,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro DNA binding assay, transfection with nuclear localization observation, luciferase reporter gene assay\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus reporter assay plus nuclear localization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16730372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR from isolated cell populations, primer extension assay to identify transcription start site, promoter-luciferase reporter co-transfection assay\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter mapping with reporter assay and co-transfection, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18004979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, functional gain/loss-of-function with multiple phenotypic readouts, in vivo xenograft, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24419085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino knockdown in zebrafish, rescue experiments with GRHL1 and DSG1, electron microscopy, hair cell apoptosis assay\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific phenotypic readout, pathway placement via rescue with target gene DSG1, ultrastructural validation, multiple orthogonal methods\",\n      \"pmids\": [\"25896282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, mutagenesis of phosphorylation site, nuclear translocation, RNA-seq, multiple orthogonal methods in one study, single lab\",\n      \"pmids\": [\"33931584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ITC with mutagenesis confirms binding, but single lab and novel finding not yet replicated\",\n      \"pmids\": [\"38049725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, ChIP, nuclear translocation assay, functional readout; single lab, findings not yet independently replicated\",\n      \"pmids\": [\"42207451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GRHL1 (also known as LBP-32/MGR/TFCP2L2) is a transcription factor that binds DNA via a defined binding domain (including non-canonical sites lacking the CNNG core motif) and localizes to the nucleus upon activation; it is phosphorylated at Ser76 by the EGFR-ERK axis to promote nuclear translocation, where it directly binds promoters to regulate target genes including P450scc (repression), cell cycle genes (activation via CCND1), and DSG1 (desmosome formation); its transcription is repressed by an HDAC3/MYCN complex at its promoter, and it acts as a tumor suppressor in neuroblastoma while playing essential roles in inner ear epithelial integrity via desmosome regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #4]. 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 [#5]. 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 [#4]. At individual promoters its output is context-specific — it represses the human P450scc promoter [#0] while activating Cyclin D1 (CCND1) and other proliferation genes [#4, #6]. 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 [#3]. 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 [#2]. Its own promoter is positively cross-regulated by related LBP family factors LBP-1b and LBP-9 [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established GRHL1 as a nuclear, sequence-specific DNA-binding protein with transcriptional repressor activity, defining it as a functional transcription factor.\",\n      \"evidence\": \"In vitro DNA binding to the P450scc promoter, nuclear localization in transfected cells, and luciferase reporter repression\",\n      \"pmids\": [\"16730372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous occupancy of the P450scc promoter not demonstrated\", \"Mechanism of repression (cofactors) not identified\", \"Limited to a single target promoter in vitro\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"RT-PCR from isolated placental cells, primer extension to map transcription start, and promoter-luciferase co-transfection with LBP-1b and LBP-9\",\n      \"pmids\": [\"18004979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of LBP-1b/LBP-9 to the GRHL1 promoter not shown\", \"Functional consequence of cross-regulation in vivo unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP for HDAC3/MYCN and histone acetylation, genome-wide expression profiling, gain/loss-of-function in cell lines, and xenograft assays\",\n      \"pmids\": [\"24419085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GRHL1 target genes mediating tumor suppression not pinpointed\", \"Whether MYCN repression of GRHL1 occurs in patient tumors not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish, rescue with GRHL1 and DSG1, electron microscopy of desmosomes, and hair cell apoptosis assay\",\n      \"pmids\": [\"25896282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GRHL1 binding to the DSG1 promoter not shown in this study\", \"Conservation of this axis in mammalian inner ear not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNA-seq after knockdown, ChIP for promoter binding, Ser76 site-directed mutagenesis, nuclear translocation and EGF stimulation assays\",\n      \"pmids\": [\"33931584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase directly phosphorylating Ser76 not biochemically identified\", \"Reconciliation with tumor-suppressor role in neuroblastoma not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Redefined GRHL1 DNA-binding specificity by demonstrating direct binding to non-canonical sites lacking the CNNG core motif, broadening its potential target repertoire.\",\n      \"evidence\": \"Deep-learning model trained on HT-SELEX and ChIP-Seq, with isothermal titration calorimetry and mutagenesis on the GRHL1 DNA-binding domain\",\n      \"pmids\": [\"38049725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional regulation of genes via non-canonical sites in cells not shown\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"tsRNA-Gly overexpression/knockdown, Co-IP of the ACPH-tsRNA-Gly complex, nuclear translocation assay, ChIP for CCND1 promoter, and liver regeneration assays\",\n      \"pmids\": [\"42207451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ACPH/tsRNA-Gly to GRHL1 translocation not resolved\", \"Single lab, not independently replicated\", \"Relationship to EGFR-ERK/Ser76 pathway unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DSG1\", \"CCND1\", \"MYCN\", \"HDAC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}