Affinage

GLI1

Zinc finger protein GLI1 · UniProt P08151

Length
1106 aa
Mass
117.9 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLI1 is a zinc-finger transcription factor that serves as the principal transcriptional activator of the vertebrate Hedgehog (Hh) signaling pathway, coupling extracellular Shh signals to gene expression programs that control embryonic patterning, stem cell proliferation, and tumorigenesis. GLI1 is positioned downstream of Sonic hedgehog and upstream of the receptor Patched (PTCH1), and its transcriptional output—including target genes PTCH1, DNMT1, SOX2, basonuclin, NEK2A, and BMP2—is governed by a multilayered post-translational regulatory network: sequential phosphorylation by PKA, GSK3, and CKI generates a β-TrCP degron that triggers ubiquitin–proteasome-mediated processing into a repressor form, while AMPK phosphorylation independently promotes β-TrCP-dependent degradation and cytoplasmic retention; conversely, deubiquitinases USP48 and USP21 stabilize GLI1 protein, with USP48 forming a positive-feedback loop through GLI1-dependent transcriptional induction (PMID:17102630, PMID:28562331, PMID:28623188, PMID:27621083). ERK2 phosphorylation of three conserved sites near the SUFU-binding region weakens GLI1–SUFU interaction by over 25-fold, releasing GLI1 for nuclear accumulation, while MEKK2/3 phosphorylation has the opposite effect of enhancing SUFU association and reducing DNA binding; additional modulators include ADAR1-mediated RNA editing, PRMT1/5-dependent arginine methylation, and O-GlcNAcylation, all of which tune GLI1 transcriptional potency (PMID:35831023, PMID:29662197, PMID:29203771, PMID:32859041, PMID:30420690). Constitutive GLI1 activation—whether by overexpression, stabilizing mutations that remove its proteasomal degradation signals, or oncogenic gene fusions—is sufficient to drive basal cell carcinoma formation in transgenic mice and contributes to medulloblastoma and other malignancies (PMID:10725363, PMID:16421275, PMID:27101025).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1996 High

    Placing GLI1 within the Hedgehog cascade answered where the transcription factor sits relative to ligand and receptor: Shh induces GLI1, and GLI1 in turn activates Patched expression, establishing GLI1 as the principal downstream effector of vertebrate Hh signaling.

    Evidence In situ hybridization and ectopic Shh expression in chick limb buds with epistasis analysis

    PMID:8948590

    Open questions at the time
    • No biochemical mechanism for how Shh signal reaches GLI1
    • GLI1 vs GLI2/3 functional redundancy not resolved
    • Mammalian in vivo validation not yet performed
  2. 1998 High

    Establishing that GLI1 has unique activator functions antagonized by GLI2/GLI3 repressor activity resolved how combinatorial Gli codes pattern the neural tube, showing GLI family members are not interchangeable.

    Evidence mRNA co-injection epistasis in Xenopus embryos with floor plate and ventral neuron markers

    PMID:9584120

    Open questions at the time
    • Molecular basis of GLI1 vs GLI2/3 activator/repressor specificity unknown
    • No post-translational mechanism yet described
  3. 2000 High

    Demonstrating that GLI1 overexpression alone drives basal cell carcinoma in mouse skin, without p53 or Ras co-mutations, established GLI1 as a bona fide primary oncogene and linked aberrant Hh pathway output to cancer.

    Evidence Transgenic mouse skin-specific GLI1 overexpression with histopathology and oncogene mutation analysis

    PMID:10725363

    Open questions at the time
    • Endogenous mechanisms leading to GLI1 overactivation in human BCC not addressed
    • Downstream transcriptional targets driving tumorigenesis unidentified
  4. 2001 High

    Identification of Zic proteins as zinc-finger-domain-mediated physical interactors that translocate GLI to the nucleus revealed a non-canonical input that modulates GLI subcellular localization and transcriptional activity.

    Evidence Co-immunoprecipitation, colocalization, and transcriptional reporter assays

    PMID:11238441

    Open questions at the time
    • Physiological context for Zic-GLI interaction unclear
    • Whether Zic proteins affect GLI1 vs GLI2/3 differentially unknown
  5. 2004 Medium

    Identification of basonuclin as a direct GLI transcriptional target linking Hh signaling to rRNA synthesis provided the first mechanistic connection between GLI activity and ribosome biogenesis in cancer.

    Evidence GLI binding to basonuclin promoter, rRNA quantification, BCC immunostaining

    PMID:15313903

    Open questions at the time
    • Whether rRNA upregulation is necessary for GLI1-driven tumorigenesis untested
    • Contribution of individual GLI family members not resolved
  6. 2006 High

    Discovery of two independent proteasomal degradation signals (D(N) and D(C)) and the reconstitution of PKA→GSK3→CKI sequential phosphorylation creating a β-TrCP degron defined the core ubiquitin–proteasome axis controlling GLI1 protein levels and repressor/activator balance.

    Evidence Mutagenesis of degrons with transgenic tumor assays; biochemical reconstitution of phosphorylation and ubiquitination in Drosophila and mammalian cells

    PMID:16421275 PMID:17102630

    Open questions at the time
    • Relative contribution of D(N) vs D(C) in physiological contexts unclear
    • Whether processing produces a functional repressor from GLI1 (vs GLI3) debated
  7. 2006 Medium

    PTCH1 was found to inhibit GLI1 transcriptional activity through a Smoothened-independent, SUFU-independent mechanism, revealing an additional layer of pathway feedback that could not be explained by the canonical signal relay.

    Evidence Reporter assays with cyclopamine and PTCH1 deletion constructs, SUFU knockdown

    PMID:16229683

    Open questions at the time
    • Molecular mechanism of Smo-independent PTCH1 inhibition of GLI1 unresolved
    • Not independently replicated
  8. 2008 Medium

    PKCδ was placed as a negative regulator acting downstream of Smoothened to inhibit GLI1 transcriptional output, expanding the kinase network controlling GLI1 beyond PKA/GSK3/CKI.

    Evidence Gli-luciferase reporter, PKCδ siRNA/overexpression, epistasis with cyclopamine

    PMID:19015273

    Open questions at the time
    • Direct phosphorylation sites on GLI1 not mapped
    • Mechanism of inhibition (stability, localization, or DNA binding) not distinguished
  9. 2011 High

    Gli1 knockout mice revealed a physiological role for GLI1 in HSC proliferation and myeloid differentiation, extending GLI1 function beyond embryonic patterning and cancer to adult stem cell homeostasis.

    Evidence Gli1 null mice, HSC transplantation, colony formation, Cyclin D1 analysis

    PMID:20107231

    Open questions at the time
    • Whether GLI1 acts cell-autonomously in HSCs vs niche cells not fully resolved
    • Compensatory roles of GLI2 in hematopoiesis not excluded
  10. 2011 Medium

    ChIP demonstration that GLI1 directly binds the DNMT1 promoter and controls DNMT1/DNMT3a expression connected Hh-GLI1 signaling to epigenetic reprogramming via DNA methylation in pancreatic cancer.

    Evidence ChIP, siRNA/overexpression of GLI1, methylation-specific PCR for APC in pancreatic cancer cells

    PMID:22110720

    Open questions at the time
    • Genome-wide methylation consequences of GLI1 activation not mapped
    • Causal role of DNMT1 upregulation in GLI1-driven tumorigenesis not demonstrated
  11. 2014 High

    Genome-scale screening identified Arhgap36 as a Smoothened-independent activator of Gli that requires cilia and interacts with SUFU, revealing non-canonical inputs into the Gli activation cascade.

    Evidence Genome-scale cDNA screen, Smo inhibitor and cilia-KO epistasis, SUFU co-immunoprecipitation

    PMID:25024229

    Open questions at the time
    • Whether Arhgap36 directly binds GLI1 or acts only through SUFU unclear
    • Physiological tissues where Arhgap36-Gli pathway operates not defined
  12. 2015 Medium

    Stabilized β-catenin was shown to physically sequester GLI1 and inhibit its transcriptional activity, uncovering a direct Wnt–Hh crosstalk mechanism at the protein–protein level.

    Evidence Co-immunoprecipitation, proximity ligation assay, Gli reporter, medulloblastoma cell proliferation assays

    PMID:25645196

    Open questions at the time
    • Binding interface not mapped
    • Whether endogenous Wnt activation levels are sufficient for GLI1 sequestration unknown
  13. 2016 High

    Two deubiquitinase inputs—USP48 forming a positive feedback loop and USP21 localizing GLI1 to the centrosome for PKA-mediated phosphorylation—revealed that GLI1 protein stability is actively maintained by DUB activity, not merely by absence of ubiquitination.

    Evidence Co-immunoprecipitation, deubiquitination assays, centrosome localization, transcriptional reporters

    PMID:27621083 PMID:28623188

    Open questions at the time
    • Whether USP48 and USP21 act on the same or distinct ubiquitin chain types unclear
    • In vivo significance of centrosomal GLI1 regulation not tested
  14. 2016 Medium

    The MALAT1-GLI1 translocation producing a truncated but transcriptionally active GLI1 fusion defined a novel oncogenic mechanism in plexiform fibromyxoma, showing that structural rearrangements can bypass normal GLI1 regulatory controls.

    Evidence Genomic PCR, FISH, Sanger sequencing, immunohistochemistry, transcriptional activity assay

    PMID:27101025

    Open questions at the time
    • Frequency of this fusion across tumor types not established
    • Whether fusion escapes proteasomal regulation not tested
  15. 2017 High

    AMPK phosphorylation of GLI1 was shown to promote β-TrCP interaction, ubiquitination, and cytoplasmic retention, linking cellular energy sensing to Hh pathway attenuation through a mechanism converging on the same degron used by PKA/GSK3/CKI.

    Evidence Phosphomimetic/alanine mutagenesis, co-immunoprecipitation with β-TrCP, ubiquitination assay, nuclear fractionation

    PMID:28562331

    Open questions at the time
    • AMPK phosphorylation sites vs PKA/GSK3/CKI sites not shown to be identical or distinct
    • In vivo metabolic conditions that activate this axis not defined
  16. 2017 High

    ADAR1-mediated A-to-I RNA editing of GLI1 transcripts was shown to enhance GLI1 transcriptional activity and drive drug resistance in myeloma, establishing post-transcriptional RNA modification as a previously unrecognized regulatory layer.

    Evidence RNA editing assay, catalytically dead ADAR1 mutant, GLI1 reporter, patient-derived xenografts

    PMID:29203771

    Open questions at the time
    • Specific edited nucleotide(s) and their effect on GLI1 protein function not fully mapped
    • Whether RNA editing of GLI1 operates outside myeloma context unknown
  17. 2018 High

    MEKK2/3 phosphorylation of GLI1 was found to reduce protein stability, DNA binding, and increase SUFU association—opposite to the ERK2 effect—establishing that distinct MAP kinase cascades have opposing effects on GLI1 activity.

    Evidence In vitro kinase assay, mutagenesis, DNA-binding assay, co-immunoprecipitation with SUFU, medulloblastoma proliferation assays

    PMID:29662197

    Open questions at the time
    • Whether MEKK2/3 and ERK2 phosphorylation sites overlap or are exclusive not resolved
    • Physiological signals routing through MEKK2/3 to GLI1 not identified
  18. 2018 Medium

    O-GlcNAcylation of GLI1 under hyperglycemic conditions was shown to enhance transcriptional activity, connecting nutrient-sensing glycosylation to Hh pathway output.

    Evidence O-GlcNAc modification assay, OGT/OGA inhibition, GLI reporter, PKM2 knockdown

    PMID:30420690

    Open questions at the time
    • Specific O-GlcNAcylated residues not identified
    • Interplay with phosphorylation-dependent regulation unknown
  19. 2019 Medium

    Genome-wide ChIP-seq in chondrosarcoma cells defined the direct GLI1 transcriptome, revealing that GLI1 and GLI2 share many but not all targets (including BMP2) and identifying Hh–BMP signaling crosstalk through shared binding regions.

    Evidence ChIP-seq for GLI1 and GLI2, microarray, cross-species conservation analysis

    PMID:30695055

    Open questions at the time
    • Whether GLI1/GLI2 target specificity varies across cell types not addressed
    • Functional validation of most identified targets not performed
  20. 2019 High

    Reconstitution of Fu/ULK3-family kinase phosphorylation of Gli showed that activating phosphorylation promotes CK1-dependent secondary modifications, weakens SUFU binding, and recruits the coactivator CBP, providing a mechanistic basis for the Hh-induced activator switch.

    Evidence In vitro kinase assay, mutagenesis, co-immunoprecipitation, Drosophila–mammalian epistasis, ciliary localization

    PMID:31279575

    Open questions at the time
    • Whether ULK3 directly phosphorylates GLI1 (vs GLI2/Ci) at the same efficiency unclear
    • Structural basis for how phosphorylation weakens SUFU binding not resolved
  21. 2020 Medium

    PRMT1 and PRMT5 were shown to methylate GLI1 on arginine residues with distinct functional outcomes—PRMT1 enhancing transcriptional activity and PRMT5 promoting protein stabilization—adding arginine methylation to the post-translational code governing GLI1.

    Evidence Arginine methylation assay, PRMT1/5 gain- and loss-of-function, target gene expression readouts

    PMID:32859041

    Open questions at the time
    • Specific methylated arginine residues not mapped
    • Whether methylation cross-talks with phosphorylation or ubiquitination not tested
  22. 2022 High

    ERK2 phosphorylation of three conserved sites near the SUFU-binding region was shown to weaken GLI1–SUFU interaction over 25-fold, providing a quantitative biophysical mechanism for how MAPK signaling releases GLI1 from cytoplasmic sequestration.

    Evidence In vitro kinase assay, phosphomimetic mutagenesis, binding affinity measurements, transcriptional reporters

    PMID:35831023

    Open questions at the time
    • In vivo physiological contexts where ERK2-GLI1 axis operates not defined
    • Whether ERK2 also regulates GLI2/3–SUFU interactions not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and kinetic model integrating the multiple post-translational inputs (phosphorylation by ≥6 kinases, ubiquitination/deubiquitination, methylation, O-GlcNAcylation, RNA editing) into a coherent regulatory code that predicts GLI1 output in specific cellular contexts remains to be established.
  • No structural model of full-length GLI1 with post-translational modifications exists
  • Quantitative integration of activating vs inhibitory inputs not modeled
  • Cell-type-specific chromatin context governing GLI1 target selection largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
ADARBTRCCTNNB1PRMT1PRMT5SUFUUSP21USP48

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 GLI1 protein is rapidly destroyed by the proteasome through two independent degradation signals (D(N) and D(C)); removal of both signals stabilizes GLI1 protein and accelerates basal cell carcinoma tumor formation in transgenic mice. Mutagenesis of degradation signals, transgenic mouse tumor assays, proteasome inhibitor experiments Genes & development High 16421275
2006 Sequential phosphorylation of GLI1 by PKA, GSK3, and CKI creates docking sites that recruit SCF(β-TRCP) ubiquitin ligase, promoting GLI1 ubiquitination and proteasome-mediated processing into a transcriptional repressor. Biochemical reconstitution, phosphorylation assays, ubiquitination assays in Drosophila and mammalian cells Cell cycle High 17102630
2001 Zic family proteins physically interact with GLI proteins through their zinc finger domains; coexpressed Zic proteins translocate GLI proteins to the nucleus and mutually regulate each other's transcriptional activity. Co-immunoprecipitation, colocalization/nuclear translocation assay, transcriptional reporter assays The Journal of biological chemistry High 11238441
1996 Sonic hedgehog up-regulates GLI1 transcription in limb bud mesenchyme, and activated GLI1 induces expression of Patched, placing GLI1 downstream of Shh and upstream of Patched as a key transcription factor in the vertebrate hedgehog signaling pathway. In situ hybridization, ectopic gene expression in chick limb buds, genetic epistasis Developmental biology High 8948590
1998 In Xenopus, GLI1 specifically induces floor plate differentiation and ventral forebrain neuron identity; GLI2 and GLI3 antagonize GLI1 function by repressing ectopic floor plate induction, establishing combinatorial Gli control of neural tube patterning. mRNA injection epistasis in Xenopus embryos, co-injection repression assays, marker gene expression Development High 9584120
2000 Ectopic overexpression of human GLI1 in mouse skin is sufficient to induce basal cell carcinomas and trichoepitheliomas without requiring additional p53 or Ha-ras mutations, establishing GLI1 as a primary oncogenic driver. Transgenic mouse overexpression, histopathology, p53 and ras mutation analysis Proceedings of the National Academy of Sciences of the United States of America High 10725363
2006 PTCH1 inhibits GLI1 transcriptional activity through a mechanism independent of Smoothened (cyclopamine-insensitive) and Suppressor of Fused (SUFU); deletion mapping identified PTCH1 domains (aa 180–786 and 1058–1210) required for this inhibition. Reporter assays, cyclopamine treatment, PTCH1 deletion constructs, SUFU knockdown The Biochemical journal Medium 16229683
2008 Protein kinase Cδ (PKCδ) negatively regulates hedgehog signaling by inhibiting GLI1 transcriptional activity downstream of Smoothened; activated PKCδ decreases Gli-luciferase reporter activity and reduces endogenous GLI1 and PTCH1 expression. Luciferase reporter assay, PKCδ siRNA/overexpression, epistasis with cyclopamine (Smo antagonist) The Journal of biological chemistry Medium 19015273
2011 Gli1 null mice have increased quiescent long-term HSCs with enhanced engraftment, but impaired myeloid development and reduced Cyclin D1 levels, demonstrating that Gli1 regulates hematopoietic stem cell proliferation and myeloid progenitor function. Gli1 knockout mouse, HSC transplantation assays, colony formation, G-CSF response, Cyclin D1 western blot Blood High 20107231
2017 The deubiquitinase USP48 stabilizes GLI1 protein by directly interacting with GLI1 and cleaving its ubiquitin chains; SHH pathway induces USP48 expression through GLI1-mediated transcriptional activation, forming a positive feedback loop. Co-immunoprecipitation, deubiquitination assay, USP48 knockdown with Gli-target gene readouts, USP48 overexpression EMBO reports High 28623188
2016 USP21 deubiquitylase interacts with GLI1 and KCTD6; both overexpression and depletion of catalytically active USP21 suppress Gli1-dependent transcription. USP21 recruits and stabilizes GLI1 at the centrosome where it promotes GLI1 phosphorylation by PKA, implicating the centrosome as a hub for GLI1 regulation. Co-immunoprecipitation, GLI1-reporter assays, USP21 depletion/overexpression, centrosome localization experiments Journal of cell science Medium 27621083
2017 AMPK phosphorylates GLI1 at multiple sites (GLI13E phosphomimetic mutant), promoting interaction with β-TrCP E3 ligase, GLI1 ubiquitination and proteasomal degradation; AMPK also inhibits GLI1 nuclear localization. Mutagenesis (phosphomimetic/alanine substitutions), co-immunoprecipitation, ubiquitination assay, nuclear/cytoplasmic fractionation Oncotarget High 28562331
2018 MEKK2 and MEKK3 phosphorylate GLI1 on multiple Ser/Thr sites, reducing GLI1 protein stability, DNA-binding ability, and increasing its association with SUFU, thereby inhibiting GLI1 transcriptional activity and medulloblastoma cell proliferation. In vitro kinase assay, mutagenesis, Co-immunoprecipitation, DNA-binding assay, cell proliferation assays Oncogene High 29662197
2019 Fu-family kinases (Drosophila Fu and mammalian ULK3/STK36) phosphorylate Gli/GLI2 on conserved sites (e.g., Ser218 and Ser1230 on Ci), promoting further CK1-mediated phosphorylation; these events alter SUFU binding, facilitate recruitment of Transportion and transcriptional coactivator CBP, and activate Gli transcription factor. Mammalian SHH activates Gli2 via ULK3/mFu in a ciliary-localization-dependent manner. In vitro kinase assay, mutagenesis, co-immunoprecipitation, Drosophila and mammalian epistasis, ciliary localization experiments Developmental cell High 31279575
2022 ERK2 MAP kinase phosphorylates GLI1 on three conserved sites (S102, S116, S130) near the high-affinity SUFU binding region; cooperative multisite phosphorylation weakens GLI1-SUFU binding by over 25-fold and enhances GLI1 transcriptional activity in mammalian cells. In vitro kinase assay, mutagenesis (phosphomimetic substitutions), binding affinity measurements, transcriptional reporter assays Life science alliance High 35831023
2015 Stabilized β-catenin physically interacts with GLI1 protein, leading to GLI1 sequestration and inhibition of its transcriptional activity, resulting in reduced Hedgehog target gene expression, reduced proliferation, G2/M arrest, and a senescent-like state in medulloblastoma cells. Co-immunoprecipitation, proximity ligation assay, Gli-reporter assay, sphere self-renewal assay, cell cycle analysis Molecular cancer Medium 25645196
2014 Arhgap36 acts in a Smoothened-independent manner to inhibit Gli repressor formation and promote activation of full-length Gli proteins; it requires kinesin family member 3a and IFT88 (ciliogenesis factors) and functionally/biochemically interacts with Suppressor of Fused (SUFU). Genome-scale cDNA overexpression screen, epistasis with Smo inhibitors, cilia KO epistasis, co-immunoprecipitation with SUFU, transcriptional profiling Proceedings of the National Academy of Sciences of the United States of America High 25024229
2011 GLI1 directly binds the DNMT1 promoter (shown by ChIP assay) and regulates DNMT1 and DNMT3a expression in pancreatic cancer; GLI1 modulation (via siRNA, cyclopamine, or overexpression) proportionally changes DNMT1/DNMT3a mRNA and protein, and GLI1-dependent DNMT1 upregulation affects APC gene methylation. Chromatin immunoprecipitation (ChIP), siRNA knockdown, lentiviral overexpression, western blot, methylation-specific PCR PloS one Medium 22110720
2017 ADAR1-mediated Alu-dependent adenosine-to-inosine RNA editing of GLI1 enhances its transcriptional activity; wild-type but not catalytically mutant ADAR1 promotes GLI1 editing and Hedgehog pathway activation, driving immunomodulatory drug resistance in multiple myeloma. RNA editing assay, ADAR1 wild-type vs. mutant expression, GLI1 transcriptional reporter, patient-derived xenograft transplantation Nature communications High 29203771
2016 MALAT1-GLI1 translocation produces a truncated GLI1 fusion protein that is overexpressed and retains capacity to transcriptionally activate GLI1 target genes, defining an oncogenic mechanism in plexiform fibromyxoma. PCR on genomic DNA, Sanger sequencing, FISH, immunohistochemistry, transcriptional activity assay of fusion protein The Journal of pathology Medium 27101025
2018 GLI proteins (GLI1 or GLI2) are associated with a Gli binding site within the SOX2 promoter (shown by ChIP), and GLI1/GLI2 downregulation reduces SOX2 expression and tumor sphere formation in gemcitabine-resistant pancreatic cancer cells. Chromatin immunoprecipitation (ChIP), GLI1/2 siRNA knockdown, tumor sphere formation assay Oncogene Medium 30382189
2019 GLI1 and GLI2 bind six conserved Gli binding sites (GBS) in the first intron of the human GLI1 gene in vitro; elimination of GBS1 and GBS4 attenuates transcriptional activation by GLI1, and GLI1 also binds the histone variant H2A.Z, suggesting autoregulation of GLI1 through chromatin-associated mechanisms. In vitro GLI binding assay, mutagenesis of GBS sites in reporter constructs, H2A.Z co-immunoprecipitation DNA repair Medium 31085420
2018 O-GlcNAcylation of GLI1 (and GLI2) under hyperglycemic conditions enhances their transcriptional activity; inhibiting O-GlcNAc transferase reduces GLI activity while inhibiting O-GlcNAcase increases it, and PKM2 directly influences GLI1 activity in elevated glucose conditions. O-GlcNAc modification assay, OGT/OGA inhibition, GLI-reporter assay, PKM2 knockdown Laboratory investigation Medium 30420690
2020 PRMT1 methylates GLI1 to upregulate its transcriptional activity and target gene expression; cytoplasmic PRMT5 methylates GLI1 and promotes GLI1 protein stabilization. Arginine methylation assay, PRMT1/PRMT5 loss-of-function and overexpression, GLI-target gene expression Cells Medium 32859041
2016 Nek2A stabilizes Suppressor of Fused (SUFU, a negative regulator of Gli) by impairing ubiquitin/proteasome degradation of SUFU; Gli1 and Gli2 directly bind to the NEK2A gene promoter (by ChIP) and induce its transcription, forming a negative feedback loop in Hh signaling. ChIP, luciferase reporter assay, SUFU ubiquitination assay, Nek2A knockdown International journal of oncology Medium 28035348
2022 ULK3-dependent activation of GLI1 contributes to transcriptional upregulation of DNMT3A upon autophagy induction; shown by proximity ligation assay (PLA) for ULK3-GLI1 interaction and ChIP for GLI1 binding to DNMT3A gene. Proximity ligation assay, ChIP, shRNA knockdown, GLI1 reporter assay Autophagy Medium 35226587
2019 GLI1 and GLI2 ChIP-seq in neoplastic chondrocytes (human chondrosarcoma) identified 204 upregulated and 106 downregulated Hh-responsive target genes; overlapping targets include BMP2, revealing cross-talk between TGF-β/BMP and Hh signaling through shared GLI binding regions. ChIP-seq, microarray, bioinformatic integration with mouse Gli ChIP-on-chip PloS one Medium 30695055
2004 GLI proteins activate transcription of the basonuclin gene through a Gli-binding site in its promoter; increased basonuclin expression in turn augments rRNA transcription (47S pre-rRNA levels) in basal cell carcinoma, linking Hedgehog-GLI signaling to enhanced rRNA synthesis in cancer. Promoter deletion analysis, GLI protein binding assay, rRNA quantification, immunostaining in BCC Cancer research Medium 15313903
2022 GLI3 repressor activity is inert prior to HH signaling onset in developing limb: GLI3 binds target chromatin but loss of Gli3 does not increase target gene expression, enhancer acetylation, or chromatin accessibility before HH induction, contradicting the default-repression model. ChIP-seq (GLI3 binding), H3K27ac/chromatin accessibility profiling, Gli3 conditional knockout, gene expression in limb buds Nature communications High 35145123
2019 GLI1 ChIP-seq binding regions identified in neoplastic chondrocytes overlap with mouse Gli binding data, defining conserved direct transcriptional targets including BMP2; GLI1 transcriptional targets are partly distinct from GLI2 targets, suggesting non-redundant regulatory roles. ChIP-seq, microarray, cross-species conservation analysis PloS one Medium 30695055

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature reviews. Cancer 592 12044012
2011 Gli proteins in development and disease. Annual review of cell and developmental biology 576 21801010
2016 Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers 460 26891329
1993 Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer research 362 8221695
1996 Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Developmental biology 327 8948590
2000 Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proceedings of the National Academy of Sciences of the United States of America 321 10725363
2007 The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends in cell biology 304 17845852
2002 Hedgehog-Gli signalling and the growth of the brain. Nature reviews. Neuroscience 288 11823802
2017 Gli1 identifies osteogenic progenitors for bone formation and fracture repair. Nature communications 283 29230039
1998 Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog. Development (Cambridge, England) 205 9584120
1999 Gli proteins and Hedgehog signaling: development and cancer. Trends in genetics : TIG 204 10498938
2012 Hedgehog-Gli pathway activation during kidney fibrosis. The American journal of pathology 179 22342522
2021 Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease. Cancers 178 34298625
2006 Dual degradation signals control Gli protein stability and tumor formation. Genes & development 159 16421275
2001 Physical and functional interactions between Zic and Gli proteins. The Journal of biological chemistry 158 11238441
2020 Hedgehog Signaling and Truncated GLI1 in Cancer. Cells 153 32957513
2006 The Wnt/beta-catenin pathway regulates Gli-mediated Myf5 expression during somitogenesis. Development (Cambridge, England) 147 16936075
1999 Gli genes in development and cancer. Oncogene 147 10630638
2019 Gli Proteins: Regulation in Development and Cancer. Cells 145 30754706
2017 Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis. Journal of the American Society of Nephrology : JASN 144 28768710
2020 Gli1+ Periodontium Stem Cells Are Regulated by Osteocytes and Occlusal Force. Developmental cell 124 32652075
2015 Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms. Nature communications 120 25833741
2016 Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-regulation define a subset of plexiform fibromyxoma. The Journal of pathology 109 27101025
2017 Gastroblastoma harbors a recurrent somatic MALAT1-GLI1 fusion gene. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 106 28731043
2017 Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nature communications 106 29203771
2006 Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell cycle (Georgetown, Tex.) 102 17102630
1999 Expression of sonic hedgehog, patched, and Gli1 in developing taste papillae of the mouse. The Journal of comparative neurology 102 10096602
2015 Targeting GLI factors to inhibit the Hedgehog pathway. Trends in pharmacological sciences 101 26072120
2012 Hedgehog pathway and GLI1 isoforms in human cancer. Discovery medicine 101 22369969
2019 GLI1-amplifications expand the spectrum of soft tissue neoplasms defined by GLI1 gene fusions. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 99 31189998
2010 Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood 99 20107231
2006 Hedgehog signalling: how to get from Smo to Ci and Gli. Trends in cell biology 99 16516476
2006 Overlapping and distinct transcriptional regulator properties of the GLI1 and GLI2 oncogenes. Genomics 88 16434164
2011 Expression of DNMT1 and DNMT3a are regulated by GLI1 in human pancreatic cancer. PloS one 73 22110720
2017 Gli1-induced deubiquitinase USP48 aids glioblastoma tumorigenesis by stabilizing Gli1. EMBO reports 72 28623188
2011 Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Science signaling 72 22114144
2019 Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy. Cancers 70 30991683
2007 Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas. World journal of gastroenterology 68 17461467
2018 The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer. Oncogene 67 30382189
2014 Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 63 25552484
2015 Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance. Cancers 62 26633513
2023 The Critical Role of The Piezo1/β-catenin/ATF4 Axis on The Stemness of Gli1+ BMSCs During Simulated Microgravity-Induced Bone Loss. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 58 37759400
2017 Enthesis regeneration: a role for Gli1+ progenitor cells. Development (Cambridge, England) 56 28219952
2013 Essential role of Gli proteins in glioblastoma multiforme. Current protein & peptide science 55 23544423
2019 Phosphorylation of Ci/Gli by Fused Family Kinases Promotes Hedgehog Signaling. Developmental cell 53 31279575
2020 The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma. Expert opinion on therapeutic targets 51 32990091
2012 Gli-similar proteins: their mechanisms of action, physiological functions, and roles in disease. Vitamins and hormones 50 22391303
2015 β-Catenin-Gli1 interaction regulates proliferation and tumor growth in medulloblastoma. Molecular cancer 49 25645196
2012 Canonical and noncanonical Hedgehog/GLI signaling in hematological malignancies. Vitamins and hormones 49 22391298
2003 Emerging roles for hedgehog-patched-Gli signal transduction in reproduction. Biology of reproduction 49 12672657
2006 Inhibition of GLI1 gene activation by Patched1. The Biochemical journal 47 16229683
2005 Interference with HH-GLI signaling inhibits prostate cancer. Trends in molecular medicine 46 15882606
2020 Gli1+ Cells Couple with Type H Vessels and Are Required for Type H Vessel Formation. Stem cell reports 45 32668219
1999 Developmental pathways: Sonic hedgehog-Patched-GLI. Environmental health perspectives 45 10064544
2018 Role and inhibition of GLI1 protein in cancer. Lung Cancer (Auckland, N.Z.) 44 29628779
2014 Down-regulation of Gli-1 inhibits hepatocellular carcinoma cell migration and invasion. Molecular and cellular biochemistry 43 24792036
2019 A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth. Cancers 42 31601026
2020 Mechanosensing by Gli1+ cells contributes to the orthodontic force-induced bone remodelling. Cell proliferation 41 32472648
2022 A mineralizing pool of Gli1-expressing progenitors builds the tendon enthesis and demonstrates therapeutic potential. Cell stem cell 40 36459968
2014 Arhgap36-dependent activation of Gli transcription factors. Proceedings of the National Academy of Sciences of the United States of America 40 25024229
2019 Activating CCT2 triggers Gli-1 activation during hypoxic condition in colorectal cancer. Oncogene 38 31462707
2013 Nonclassical hedgehog-GLI signaling and its clinical implications. International journal of cancer 38 23929208
2016 The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability. Journal of cell science 37 27621083
2001 Are keloids really "gli-loids"?: High-level expression of gli-1 oncogene in keloids. Journal of the American Academy of Dermatology 37 11606920
2023 GLI1 Immunohistochemistry Distinguishes Mesenchymal Neoplasms With GLI1 Alterations From Morphologic Mimics. The American journal of surgical pathology 36 36693363
2012 Targeting hedgehog-GLI-2 pathway in osteosarcoma. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 36 22968906
2008 Protein kinase Cdelta negatively regulates hedgehog signaling by inhibition of Gli1 activity. The Journal of biological chemistry 36 19015273
2021 Alveolar Bone Marrow Gli1+ Stem Cells Support Implant Osseointegration. Journal of dental research 35 34009063
2008 Primers on molecular pathways GLI: more than just Hedgehog? Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 33 18497536
2022 GLI1 Gene Alterations in Neoplasms of the Genitourinary and Gynecologic Tract. The American journal of surgical pathology 32 34907995
2018 MEKK2 and MEKK3 suppress Hedgehog pathway-dependent medulloblastoma by inhibiting GLI1 function. Oncogene 31 29662197
2017 LepR+ cells dispute hegemony with Gli1+ cells in bone marrow fibrosis. Cell cycle (Georgetown, Tex.) 31 28976809
2004 Gli proteins up-regulate the expression of basonuclin in Basal cell carcinoma. Cancer research 29 15313903
2022 GLI1 -Rearranged Enteric Tumor : Expanding the Spectrum of Gastrointestinal Neoplasms With GLI1 Gene Fusions. The American journal of surgical pathology 28 35968961
2022 Gli1+-PDL Cells Contribute to Alveolar Bone Homeostasis and Regeneration. Journal of dental research 27 35786034
2022 Inhibiting Hh Signaling in Gli1+ Osteogenic Progenitors Alleviates TMJOA. Journal of dental research 25 35045740
2022 GLI transcriptional repression is inert prior to Hedgehog pathway activation. Nature communications 25 35145123
2022 Response of Gli1+ Suture Stem Cells to Mechanical Force Upon Suture Expansion. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 25 35443291
2020 Up-regulation of GLI1 in vincristine-resistant rhabdomyosarcoma and Ewing sarcoma. BMC cancer 24 32493277
2016 Suppression of GLI sensitizes medulloblastoma cells to mitochondria-mediated apoptosis. Journal of cancer research and clinical oncology 24 27601167
2016 Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24 27662839
2018 O-GlcNAcylation of GLI transcription factors in hyperglycemic conditions augments Hedgehog activity. Laboratory investigation; a journal of technical methods and pathology 23 30420690
2017 Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through β-TrCP-mediated proteasome degradation. Oncotarget 23 28562331
2018 A conditionally immortalized Gli1-positive kidney mesenchymal cell line models myofibroblast transition. American journal of physiology. Renal physiology 22 30303712
2021 The vital role of Gli1+ mesenchymal stem cells in tissue development and homeostasis. Journal of cellular physiology 21 33533019
2019 Unique and overlapping GLI1 and GLI2 transcriptional targets in neoplastic chondrocytes. PloS one 21 30695055
2022 ULK3-dependent activation of GLI1 promotes DNMT3A expression upon autophagy induction. Autophagy 20 35226587
2020 Gene of the month: GLI-1. Journal of clinical pathology 20 31980562
2020 Fine-Tuning of GLI Activity through Arginine Methylation: Its Mechanisms and Function. Cells 20 32859041
2020 RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1. eLife 19 32662771
2019 Regulation of GLI1 by cis DNA elements and epigenetic marks. DNA repair 18 31085420
2023 Gli1 marks a sentinel muscle stem cell population for muscle regeneration. Nature communications 17 37914731
2016 Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway. International journal of oncology 17 28035348
2022 ERK2 MAP kinase regulates SUFU binding by multisite phosphorylation of GLI1. Life science alliance 16 35831023
2020 Hedgehog pathway activation in oral squamous cell carcinoma: cancer-associated fibroblasts exhibit nuclear GLI-1 localization. Journal of molecular histology 16 33000351
2022 Gli1+ Osteogenic Progenitors Contribute to Condylar Development and Fracture Repair. Frontiers in cell and developmental biology 15 35330911
2021 Hedgehog/GLI1 signaling pathway regulates the resistance to cisplatin in human osteosarcoma. Journal of Cancer 15 34659557
2019 Regulation of Survivin Isoform Expression by GLI Proteins in Ovarian Cancer. Cells 14 30736319
2019 IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage. Cancers 14 31783569
2014 PKM2 regulates Gli1 expression in hepatocellular carcinoma. Oncology letters 14 25289083