Affinage

GADD45G

Growth arrest and DNA damage-inducible protein GADD45 gamma · UniProt O95257

Length
159 aa
Mass
17.1 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GADD45G (CR6) is a small nuclear stress-response protein and tumor suppressor that couples cell-cycle and growth control to stress-activated MAP kinase signaling (PMID:12124778, PMID:10490824). It exerts direct growth control by specifically binding the CDK1/CyclinB1 complex and inhibiting its kinase activity without disrupting the complex—a mechanistic distinction from its paralogs—and by interacting with PCNA and p21 to impede PCNA-dependent negative growth control (PMID:12124778, PMID:11022036); these activities translate into colony-formation suppression, cell-cycle arrest, and sensitization to genotoxic stress (PMID:10490824, PMID:11251170). A second, dominant arm of GADD45G function is activation of the p38 and JNK MAP kinase cascades through the upstream kinase MEKK4 (MAP3K4) (PMID:15044949, PMID:25068120). This MAPK axis is the common mechanistic thread linking GADD45G to a broad set of physiological outcomes: it drives IFN-γ production and activation-induced cell death in TH1/CD4+ T cells (PMID:11371360, PMID:15044949); specifies male sex determination via a GADD45G→p38→GATA4→SRY cascade (PMID:23102580, PMID:23102581, PMID:23516551); activates the brown-adipose thermogenic program by potentiating ERRβ/γ transcription (PMID:25071184); instructs hematopoietic stem cell differentiation (PMID:25068120); promotes p38-dependent RIP1/caspase-8 cardiomyocyte apoptosis (PMID:26370247); and supports neuronal differentiation, neurite outgrowth via a p38/CDC25B/CRMP2 module, and hippocampal memory through p38/JNK→ATF-2/c-Jun/CREB signaling (PMID:31826946, PMID:35497000). The function of GADD45G depends on dimerization through a four-helix-bundle interface defined by its αβα-sandwich crystal structure, since dimer-disrupting mutants abolish growth inhibition and abolish its interaction with E-cadherin in tumor-suppressive contexts (PMID:18445651, PMID:31562612). GADD45G expression is tightly controlled transcriptionally by C/EBPβ/δ, Ascl1, JAK3/STAT5, and NF-κB/STAT3, and is silenced epigenetically and post-transcriptionally (histone deacetylation, miR-383) in cancers including AML, where its loss impairs homologous-recombination DNA repair control (PMID:11012671, PMID:20382226, PMID:23681230, PMID:33945602, PMID:25415264).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 Medium

    Established that GADD45G has intrinsic growth-suppressive activity, framing it as a candidate tumor suppressor rather than merely a stress marker.

    Evidence Colony formation assay in H1299 lung carcinoma and cDNA cloning of the conserved murine homolog

    PMID:10490824

    Open questions at the time
    • Did not identify the molecular target mediating growth suppression
    • No mechanism for how growth arrest is enforced
  2. 2001 High

    Defined the first physiological loss-of-function role: GADD45G is required for p38/JNK activation and IFN-γ production in TH1 cells, linking it to stress-MAPK signaling and immune effector function.

    Evidence Gadd45g knockout mouse with TH1 kinase, cytokine, and contact-hypersensitivity readouts

    PMID:11371360

    Open questions at the time
    • Upstream kinase connecting TCR signaling to GADD45G not defined here
    • Direct molecular target of GADD45G in MAPK activation not identified
  3. 2000 High

    Identified the direct molecular partners (PCNA, p21) and CDK1/CyclinB1 underlying growth control, showing GADD45G inhibits CDK1 kinase without complex dissociation—distinguishing it mechanistically from paralogs.

    Evidence Co-IP, domain mapping, in vitro/in vivo binding and kinase activity assays

    PMID:11022036 PMID:12124778

    Open questions at the time
    • Structural basis of selective CDK1/CyclinB1 inhibition not resolved at this stage
    • Whether PCNA and CDK1 binding are concurrent or mutually exclusive unclear
  4. 2003 High

    Showed GADD45G acts as a scaffold by recruiting CRIF1, which co-localizes in the nucleus and additively inhibits CDK1/CyclinB1, indicating cooperative rather than solo growth control.

    Evidence GST pull-down, mammalian two-hybrid, co-IP, histone H1 kinase assay, siRNA

    PMID:12716909

    Open questions at the time
    • Stoichiometry of the GADD45G–CRIF1–CDK1 assembly unknown
    • Whether CRIF1 modulates the MAPK arm of GADD45G untested
  5. 2004 High

    Placed MEKK4 (MAP3K4) as the upstream kinase through which GADD45G activates p38, providing the missing mechanistic link between GADD45G and the stress-MAPK cascade.

    Evidence MEKK4 knockout mouse, T-cell stimulation, cytokine measurement, genetic epistasis

    PMID:15044949

    Open questions at the time
    • Whether GADD45G binds MAP3K4 directly to relieve autoinhibition not shown structurally here
    • STAT4-independence defined but full transcriptional output not mapped
  6. 2008 High

    Resolved the GADD45G structure and proved dimerization through a four-helix-bundle interface is essential for growth-inhibitory function, providing a structural prerequisite for activity.

    Evidence X-ray crystallography, dimer-disrupting mutagenesis, cell-based growth assays

    PMID:18445651

    Open questions at the time
    • Structure of GADD45G bound to CDK1/CyclinB1 or MAP3K4 not determined
    • How dimerization mechanically activates downstream kinases unresolved
  7. 2012 High

    Demonstrated a non-redundant developmental role: GADD45G drives male sex determination through a GADD45G→p38→GATA4→SRY cascade, achieving the Sry expression threshold.

    Evidence Knockout mice, in situ hybridization, ChIP of GATA4 on Sry promoter, p38 phosphorylation, MAP3K4 transgene rescue

    PMID:23102580 PMID:23102581

    Open questions at the time
    • What triggers GADD45G expression in the bipotential gonad not defined
    • Direct biochemical link from GADD45G to p38 in gonadal cells inferred from genetics
  8. 2013 High

    Confirmed strain-independent, paralog-specific requirement of GADD45G for sex determination, ruling out compensation by GADD45A/B.

    Evidence Knockout mice on pure C57BL/6 background, phenotyping, Sry RT-PCR

    PMID:23516551

    Open questions at the time
    • Does not address species generalizability beyond mouse
    • Threshold mechanism of Sry control not quantified
  9. 2014 High

    Extended the GADD45G→p38 axis to metabolism, stem-cell fate, and cell death, showing it potentiates ERRβ/γ thermogenesis in brown fat, instructs HSC differentiation via MAP3K4/p38, and drives cardiomyocyte apoptosis via RIP1/caspase-8.

    Evidence Knockout mice, cold-exposure assays, ERR reporters, single-cell videomicroscopy, AAV overexpression, MI model, p38 inhibition

    PMID:25068120 PMID:25071184 PMID:26370247

    Open questions at the time
    • How the same p38 output is channeled into divergent fates (thermogenesis vs apoptosis vs differentiation) unexplained
    • Cell-type-specific cofactors directing outcome unknown
  10. 2010 High

    Identified upstream transcriptional regulators (Ascl1, C/EBPβ/δ, JAK3/STAT5), establishing how lineage and cytokine signals induce GADD45G to couple to its effector programs.

    Evidence ChIP, E-box and C/EBP-site promoter mutagenesis, reporter assays, knockout mice

    PMID:11012671 PMID:11287618 PMID:20382226

    Open questions at the time
    • Combinatorial logic among these inputs in any single cell type not integrated
    • Quantitative contribution of each factor to baseline vs induced expression unclear
  11. 2013 Medium

    Mapped repressive transcriptional control of GADD45G, showing SIRT1-regulated NF-κB/STAT3 complexes occupy the promoter as co-repressors, linking GADD45G silencing to oncogenic signaling.

    Evidence ChIP, EMSA, siRNA, promoter reporter assays

    PMID:23681230

    Open questions at the time
    • Single-lab; physiological context of SIRT1-driven derepression not validated in vivo
    • Direct vs indirect STAT3 binding inferred from EMSA only
  12. 2015 Medium

    Diversified tumor-suppressive output, showing GADD45G induces JNK-dependent SIP1-mediated senescence in liver tumors and p38/p21-mediated proliferation control in dental epithelium.

    Evidence Overexpression, siRNA, xenograft rescue, JNK/p38 inhibitors, gene expression

    PMID:23751077 PMID:26378039

    Open questions at the time
    • Why JNK vs p38 dominates in different tissues not mechanistically resolved
    • Single-lab findings per tissue
  13. 2019 Medium

    Established GADD45G as a direct E-cadherin partner that suppresses tumor invasion in a dimerization-dependent manner, and showed it sustains hippocampal MAPK→ATF-2/c-Jun/CREB signaling for memory.

    Evidence GST pull-down, co-IP, fractionation, Transwell assays, dimer mutant; hippocampal knockdown with behavioral and kinase readouts

    PMID:31562612 PMID:31826946

    Open questions at the time
    • How a nuclear MAPK activator promotes E-cadherin membrane localization unresolved
    • Both single-lab; reciprocal in vivo validation limited
  14. 2021 Medium

    Connected GADD45G loss to AML through impaired HR DNA repair and epigenetic silencing, and showed GADD45G activates MAPK during ESC differentiation while suppressing breast cancer metastasis.

    Evidence HR repair assay, ChIP for histone acetylation, patient samples, ESC differentiation with MEK inhibition, xenograft metastasis

    PMID:33945602 PMID:34601500

    Open questions at the time
    • Direct biochemical mechanism by which GADD45G modulates HR not defined
    • Single-lab per disease context
  15. 2022 Medium

    Defined two further neurogenic mechanisms—p38/CDC25B/CRMP2-driven microtubule polymerization for neurite outgrowth and DNA-demethylation-driven NeuroD1 activation for metformin-induced neurogenesis.

    Evidence Neuronal differentiation, p38 inhibitor, CDC25B manipulation, microtubule and CRMP2 phosphorylation assays; knockout mice, bisulfite sequencing, behavior

    PMID:35497000 PMID:35511865

    Open questions at the time
    • How GADD45G engages DNA-demethylation enzymes mechanistically unresolved
    • Single-lab; integration with the MAPK arm unclear
  16. 2024 Medium

    Showed GADD45G insufficiency drives myeloid-biased HSC self-renewal and MPN-like disease via RAC2→PAK1→PI3K-AKT signaling, extending its tumor-suppressive role to a defined oncogenic cascade.

    Evidence Knockout/knockdown mice, HSC assays, pathway inhibitor experiments

    PMID:38582902

    Open questions at the time
    • Whether GADD45G directly restrains RAC2 or acts indirectly not resolved
    • Single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single dimeric GADD45G protein selectively channels its shared p38/JNK output into context-specific fates (differentiation, thermogenesis, senescence, apoptosis) and whether direct GADD45G–MAP3K4 binding mechanistically links its structure to kinase activation.
  • No structure of GADD45G bound to MAP3K4 or CDK1/CyclinB1
  • Cell-type cofactors directing divergent MAPK outcomes unidentified
  • Direct biochemical mechanism of GADD45G effects on DNA repair and demethylation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CCNB1CDH1CDK1CDKN1ACRIF1MAP3K4PCNA

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GADD45G (CR6) specifically interacts with the CDK1/CyclinB1 complex (but not other CDK/Cyclin complexes) both in vitro and in vivo, and inhibits CDK1/CyclinB1 kinase activity. Unlike GADD45A and GADD45B, GADD45G inhibits the kinase without disrupting the CDK1/CyclinB1 complex. In vitro binding assay, co-immunoprecipitation, kinase activity assay Journal of cellular physiology High 12124778
2001 GADD45G mediates activation of p38 and JNK MAP kinase pathways downstream of TCR signaling in TH1 effector cells. GADD45G-deficient TH1 cells are severely defective in p38 and JNK activation, produce markedly less IFN-γ upon restimulation, and are deficient in activation-induced cell death (AICD). GADD45G-knockout mice also display reduced contact hypersensitivity. Genetic knockout mouse, kinase activity assays, cytokine measurement, in vivo hypersensitivity model Immunity High 11371360
2000 GADD45G (CR6) interacts with PCNA via a domain shared with GADD45A and GADD45B, and also interacts with p21. Interaction of CR6 with PCNA impedes PCNA's function in negative growth control. Co-immunoprecipitation, domain mapping, functional growth assay The Journal of biological chemistry Medium 11022036
2004 GADD45G and GADD45B act through MEKK4 (MAP3K4) to activate p38 and promote IFN-γ production in CD4+ T cells. Expression of GADD45G promotes IFN-γ production in MEKK4+/+ but not MEKK4−/− cells, and this pathway is independent of STAT4. MEKK4 knockout mouse, T-cell stimulation assays, cytokine measurement, epistasis analysis The EMBO journal High 15044949
2008 Crystal structure of GADD45G reveals an αβα sandwich fold with a central five-stranded mixed β-sheet. GADD45G forms dimers through a four-helix bundle interface involving the most conserved residues. Point mutants that disrupt dimerization while preserving tertiary structure abolish growth inhibition, demonstrating that dimerization is essential for GADD45G's growth-inhibitory function. X-ray crystallography, site-directed mutagenesis, cell-based growth assays Proceedings of the National Academy of Sciences of the United States of America High 18445651
2003 CR6-interacting factor 1 (CRIF1) directly binds GADD45G (and other GADD45 family members), colocalizes with GADD45G in the nucleus, and additively inhibits CDK1/CyclinB1 kinase activity together with GADD45G. GST pull-down, mammalian two-hybrid, co-immunoprecipitation, histone H1 kinase assay, siRNA knockdown The Journal of biological chemistry High 12716909
2012 GADD45G is required for male sex determination in mice. Gadd45g-null XY mice exhibit complete gonadal sex reversal due to failure to achieve the Sry expression threshold. GADD45G functions upstream of p38 MAPK, and p38 MAPK activation is required for phosphorylation of GATA4, which in turn binds the Sry promoter to drive Sry expression. A signaling cascade GADD45G → p38 MAPK → GATA4 → SRY was established. Knockout mouse model, in situ hybridization, ChIP, p38 MAPK phosphorylation assays, genetic rescue (MAP3K4 transgene) Developmental cell High 23102580 23102581
2013 Gadd45g-deficient XY mice on a pure C57BL/6 background display complete sex reversal to female phenotype, confirming a specific (not redundant) role for Gadd45g in male sex determination through control of Sry expression. Gadd45a and Gadd45b deletions do not affect sex determination. Knockout mouse, phenotypic analysis, RT-PCR for Sry expression PloS one High 23516551
2014 GADD45G is a cold-induced activator of UCP1 and oxidative capacity in brown adipose tissue (BAT). GADD45G works by activating p38 MAPK, which potentiates ERRβ and ERRγ transcriptional function independently of PGC-1 coactivators, yet synergizes with PGC-1α to induce the thermogenic program. Gadd45g-knockout mice have defects in Ucp1 induction and thermogenic response to cold. Knockout mouse, genome-wide cDNA screen, cold-exposure assays, MAPK activity assays, ERR transcriptional reporter assays Proceedings of the National Academy of Sciences of the United States of America High 25071184
2014 GADD45G instructs differentiation of long-term repopulating hematopoietic stem cells (LT-HSCs) by specifically activating MAP3K4-mediated MAPK p38 signaling. Overexpression induces and accelerates differentiation, while absence of GADD45G enhances self-renewal. Single-cell videomicroscopy showed GADD45G expression leads to lineage commitment within 36 hours with a selective reduction in megakaryocytic-erythroid progeny. Single-cell videomicroscopy tracking, genetic overexpression and knockout, MAPK activity assays Stem cell reports High 25068120
2015 Gadd45γ overexpression in cardiomyocytes induces apoptosis, fibrosis, and left ventricular dysfunction, while genetic deletion confers resistance to ischemic injury. Mechanistically, Gadd45γ activates receptor-interacting protein 1 (RIP1) and caspase-8 in a p38 MAPK-dependent manner to promote cardiomyocyte death. Adeno-associated viral vector overexpression in vivo, knockout mouse, myocardial infarction model, Western blot for RIP1 and caspase-8 activation, p38 inhibitor experiments Cardiovascular research High 26370247
2013 SIRT1 activation reduces binding of NF-κB/STAT3 complexes to the GADD45G promoter, leading to transcriptional upregulation of GADD45G. EMSA revealed that NF-κB binds directly to the GADD45G promoter while STAT3 binds indirectly in complex with NF-κB, functioning as a co-repressor. ChIP assay, EMSA, siRNA knockdown, promoter reporter assay Cell death & disease Medium 23681230
2000 Gadd45gamma gene expression is regulated transcriptionally by C/EBPβ and C/EBPδ binding to a non-canonical C/EBP-binding site in its promoter. This was identified as a mechanism by which IL-6 induces GADD45G expression during M1 cell differentiation. EMSA, reporter gene analysis, promoter cloning, expression correlation during differentiation European journal of biochemistry Medium 11012671
2001 IL-2-induced expression of Gadd45gamma in peripheral T cells is dependent on signaling through the tyrosine kinase JAK3 and transcription factors STAT5a and STAT5b. Gadd45gamma-deficient mice develop normally with intact hematopoiesis, and Gadd45gamma-deficient T lymphocytes show normal responses to IL-2, indicating dispensability for T cell proliferation under normal conditions. Knockout mouse, genetic pathway analysis (JAK3/STAT5 signaling), T-cell proliferation and hematopoiesis assays Molecular and cellular biology Medium 11287618
2010 GADD45G is directly transcriptionally induced by the basic helix-loop-helix transcription factor Ascl1 during neuronal differentiation. Two E-box consensus sites in the Gadd45gamma promoter are required for Ascl1 regulation, and Ascl1 binding to these sites was confirmed by ChIP. Overexpression of GADD45G alone is sufficient to initiate some aspects of neuronal differentiation independent of Ascl1. Microarray, real-time PCR, chromatin immunoprecipitation (ChIP), transactivation reporter assay, gain-of-function overexpression Molecular and cellular neurosciences High 20382226
2008 GADD45G overexpression in Hep-G2 hepatoma cells activates both the p38 and JNK kinase pathways to induce G2/M arrest. Transient transfection, flow cytometry, kinase activity assays Molecular biology reports Medium 19048389
2013 GADD45G regulates dental epithelial cell proliferation through p38 MAPK-mediated upregulation of p21. Gadd45g is expressed in enamel knots, and its overexpression inhibits dental epithelial cell proliferation via the p38 MAPK/p21 axis. Expression analysis, overexpression experiments, Western blot/flow cytometry for p21 and p38, p38 inhibitor treatment Genes to cells : devoted to molecular & cellular mechanisms Medium 23751077
2015 GADD45G induces cellular senescence in liver tumor cells through transcriptional activation of SIP1 (Smad-interacting protein-1). JNK (but not p38) MAPK activation is required for GADD45G-mediated SIP1 upregulation, and SIP1 knockdown abrogates the senescence and growth-suppressive effects of GADD45G in vivo. Gain-of-function overexpression, siRNA knockdown, xenograft tumor model, JNK inhibitor treatment, gene expression analysis Oncotarget Medium 26378039
2019 GADD45G interacts directly with E-cadherin (confirmed by GST pull-down and co-immunoprecipitation), enhances E-cadherin membrane localization, and suppresses migration and invasion of esophageal squamous cell carcinoma cells. The dimer-dissociating mutant of GADD45G cannot interact with E-cadherin and loses its ability to suppress migration/invasion, linking dimerization to this function. GST pull-down, co-immunoprecipitation, subcellular fractionation, Transwell migration/invasion assay, loss- and gain-of-function Digestive diseases and sciences Medium 31562612
2019 GADD45G reduction in the hippocampus impairs MAPK pathway activity (p38 and JNK) and disrupts activation of downstream targets ATF-2, c-Jun, and CREB, leading to age-like memory deficits in mice. GADD45G is required for induction of key early- and late-response genes associated with aging. Genetic knockdown in mouse hippocampus, behavioral memory tasks, kinase activity assays, gene expression analysis The Journal of neuroscience Medium 31826946
2022 GADD45G/p38 MAPK/CDC25B signaling promotes neurite outgrowth in human neurons by facilitating microtubule polymerization through dephosphorylation of phosphorylated CRMP2 (which promotes microtubule assembly). GADD45G is highly expressed in developing human cerebral specimens. In vitro neuronal differentiation, GADD45G knockdown/overexpression, p38 inhibitor, CDC25B manipulation, microtubule polymerization assay, CRMP2 phosphorylation Western blot iScience Medium 35497000
2022 Gadd45g mediates metformin-induced neuronal differentiation of neural stem cells (NSCs) via DNA demethylation. Gadd45g increases demethylation of the NeuroD1 promoter by regulating passive and active DNA demethylation enzymes through an AMPK-independent mechanism. Genetic deficiency of Gadd45g decreases hippocampal neurogenesis and leads to spatial memory decline and depression-like behaviors in mice. Knockout mouse, lentiviral overexpression in NSCs, bisulfite sequencing, neurogenic differentiation assays, behavioral testing Stem cells (Dayton, Ohio) Medium 35511865
2024 GADD45G insufficiency in the hematopoietic system leads to enhanced growth and self-renewal of myeloid-biased hematopoietic stem cells and MPN-like phenotypes. Mechanistically, GADD45G deficiency acts through sequential activation of RAC2, PAK1, and PI3K-AKT signaling pathways. Knockout/knockdown mouse model, hematopoietic stem cell assays, pathway inhibitor experiments, signaling assays Nature communications Medium 38582902
2021 GADD45G upregulation in AML cells impairs homologous recombination DNA repair, leading to DNA damage accumulation, apoptosis, differentiation, and growth arrest. GADD45G is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9. Gain-of-function overexpression, DNA repair assay (HR assay), apoptosis/differentiation assays, ChIP for histone acetylation, cell line and patient sample analysis Blood Medium 33945602
2012 GADD45G regulates TNF-α and IL-6 production in LPS-stimulated THP-1 monocyte cells through JNK activation. Knockdown of GADD45G reduces TNF-α protein by 75% and IL-6 by 60%; overexpression increases TNF-α six-fold and IL-6 eighty-fold. JNK inhibition reduces the pro-inflammatory effects of GADD45G. Lentiviral shRNA knockdown, overexpression, ELISA for cytokines, JNK inhibitor (SP600125) Inflammation research Medium 22752116
2008 GADD45G is rapidly and strongly upregulated in renal tubular cells following ureteral obstruction. Adenovirus-mediated GADD45G expression in cultured renal tubular cells activates p38 MAPK and upregulates chemokine ligands and fibrosis-related factors including TGF-β1, matrix metalloproteinases, decorin, and BMP2. Silencing GADD45G blunts inflammatory and fibrogenic mediators and monocyte infiltration in obstructed rat kidney. Differential display, adenoviral overexpression, siRNA knockdown, rat ureteral obstruction model, cytokine/chemokine expression assays Kidney international Medium 18354378
1999 CR6/GADD45G suppresses colony formation of human lung carcinoma H1299 cells, establishing its function in negative growth control. CR6 is the murine homologue of human CR6 (GADD45G), with 97% amino acid identity, confirming evolutionary conservation. Colony formation assay, cDNA cloning, sequence analysis Oncogene Medium 10490824
2001 Ectopic expression of CR6/GADD45G causes G1 phase accumulation and retardation of cellular proliferation in the absence of genotoxic stress, and sensitizes M1 myeloblastic leukemia and H1299 lung carcinoma cells to apoptosis induced by UV, MMS, γ-irradiation, and VP16. In the absence of stress, GADD45G expression does not activate the MTK1/JNK/p38 stress cascade. Inducible expression system (IPTG), flow cytometry, apoptosis assays, kinase activity measurement International journal of oncology Medium 11251170
2014 miR-383 directly targets the 3'-UTR of GADD45G mRNA, reducing its expression. Forced expression of miR-383 decreased Gadd45g protein levels and increased cellular sensitivity to DNA damage in breast cancer cells; this was rescued by ectopic GADD45G without the 3'-UTR. miR-383 also negatively regulates Gadd45g to modulate embryonic stem cell differentiation. miRNA overexpression/inhibition, 3'-UTR luciferase reporter assay, Western blot, rescue experiment PloS one Medium 25415264
2021 Gadd45g activates MAPK signaling during mouse ESC differentiation by increasing expression of positive modulators of the MAPK pathway (Csf1r, Igf2, Fgfr3), and this differentiation effect is abolished by MEK inhibition. Additionally, GADD45G overexpression inhibits breast cancer cell invasion and metastasis in vivo. ESC differentiation assays, MEK inhibitor treatment, gene expression analysis, xenograft metastasis model Cell death discovery Medium 34601500

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. Journal of cellular physiology 282 12124778
2005 The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 192 16166418
2006 Response of catalase activity to Ag+, Cd2+, Cr6+, Cu2+ and Zn2+ in five tissues of freshwater fish Oreochromis niloticus. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 180 16581305
2001 GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity 138 11371360
1999 CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control. Oncogene 134 10490824
2012 Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Developmental cell 110 23102580
1992 Extensive editing of both processed and preprocessed maxicircle CR6 transcripts in Trypanosoma brucei. The Journal of biological chemistry 105 1730639
2004 Oxidative stress-induced apoptosis in retinal photoreceptor cells is mediated by calpains and caspases and blocked by the oxygen radical scavenger CR-6. The Journal of biological chemistry 101 15210718
2012 GADD45G functions in male sex determination by promoting p38 signaling and Sry expression. Developmental cell 95 23102581
2004 GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. The EMBO journal 90 15044949
2000 Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control. The Journal of biological chemistry 87 11022036
2003 CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle. The Journal of biological chemistry 80 12716909
2004 Loss of expression of the growth inhibitory gene GADD45gamma, in human pituitary adenomas, is associated with CpG island methylation. Oncogene 74 14647444
2010 CR6-interacting factor 1 (CRIF1) regulates NF-E2-related factor 2 (NRF2) protein stability by proteasome-mediated degradation. The Journal of biological chemistry 66 20427290
2005 The role of oxidative stress in the modulation of aryl hydrocarbon receptor-regulated genes by As3+, Cd2+, and Cr6+. Free radical biology & medicine 63 16274885
2009 Gadd45b and Gadd45g are important for anti-tumor immune responses. European journal of immunology 61 19688743
2008 Gadd45-alpha and Gadd45-gamma utilize p38 and JNK signaling pathways to induce cell cycle G2/M arrest in Hep-G2 hepatoma cells. Molecular biology reports 61 19048389
2018 An in vivo analysis of Cr6+ induced biochemical, genotoxicological and transcriptional profiling of genes related to oxidative stress, DNA damage and apoptosis in liver of fish, Channa punctatus (Bloch, 1793). Aquatic toxicology (Amsterdam, Netherlands) 60 29753883
2001 Ectopic expression of MyD118/Gadd45/CR6 (Gadd45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis. International journal of oncology 56 11251170
2021 Toxic effects of hexavalent chromium (Cr6+) on bioaccumulation, apoptosis, oxidative damage and inflammatory response in Channa asiatica. Environmental toxicology and pharmacology 49 34416396
2013 SIRT1 activation enhances HDAC inhibition-mediated upregulation of GADD45G by repressing the binding of NF-κB/STAT3 complex to its promoter in malignant lymphoid cells. Cell death & disease 49 23681230
2019 Amelioration of chromium and heat stresses in Sorghum bicolor by Cr6+ reducing-thermotolerant plant growth promoting bacteria. Chemosphere 48 31812764
2015 Gadd45γ regulates cardiomyocyte death and post-myocardial infarction left ventricular remodelling. Cardiovascular research 47 26370247
2014 GADD45γ regulates the thermogenic capacity of brown adipose tissue. Proceedings of the National Academy of Sciences of the United States of America 44 25071184
2013 Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma. International journal of cancer 41 23616123
2001 Gadd45gamma is dispensable for normal mouse development and T-cell proliferation. Molecular and cellular biology 41 11287618
2011 Gadd45a, Gadd45b and Gadd45g expression during mouse embryonic development. Gene expression patterns : GEP 37 21843656
2014 Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells. Stem cell reports 36 25068120
2004 CR6-interacting factor 1 interacts with orphan nuclear receptor Nur77 and inhibits its transactivation. Molecular endocrinology (Baltimore, Md.) 36 15459248
2014 MicroRNA-383 regulates the apoptosis of tumor cells through targeting Gadd45g. PloS one 35 25415264
2013 Gadd45g is essential for primary sex determination, male fertility and testis development. PloS one 35 23516551
2009 Antioxidant CR-6 protects against reperfusion injury after a transient episode of focal brain ischemia in rats. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 35 19904289
2020 Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6. Journal of medicinal chemistry 33 32706255
2015 The chromium accumulation and its physiological effects in juvenile rockfish, Sebastes schlegelii, exposed to different levels of dietary chromium (Cr(6+)) concentrations. Environmental toxicology and pharmacology 32 26705966
2014 Therapeutic ROS targeting of GADD45γ in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E. Cell death & disease 32 24763055
2003 GADD45gamma, down-regulated in 65% hepatocellular carcinoma (HCC) from 23 chinese patients, inhibits cell growth and induces cell cycle G2/M arrest for hepatoma Hep-G2 cell lines. Molecular biology reports 32 14672412
2021 GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML. Blood 31 33945602
2019 A protective study of curcumin associated with Cr6+ induced oxidative stress, genetic damage, transcription of genes related to apoptosis and histopathology of fish, Channa punctatus (Bloch, 1793). Environmental toxicology and pharmacology 31 31207396
2014 CR6-interacting factor 1 is a key regulator in Aβ-induced mitochondrial disruption and pathogenesis of Alzheimer's disease. Cell death and differentiation 30 25361083
2011 (--)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells. Chemical research in toxicology 30 21568272
2014 Inducement of mitosis delay by cucurbitacin E, a novel tetracyclic triterpene from climbing stem of Cucumis melo L., through GADD45γ in human brain malignant glioma (GBM) 8401 cells. Cell death & disease 29 24577085
2004 Medaka as a model system for the characterisation of cell cycle regulators: a functional analysis of Ol-Gadd45gamma during early embryogenesis. Mechanisms of development 29 15210198
2017 CR6-Interacting Factor 1 Deficiency Impairs Vascular Function by Inhibiting the Sirt1-Endothelial Nitric Oxide Synthase Pathway. Antioxidants & redox signaling 27 28117598
2011 Gadd45a and Gadd45g regulate neural development and exit from pluripotency in Xenopus. Mechanisms of development 27 21854844
1999 Molecular cloning of rat GADD45gamma, gene induction and its role during neuronal cell death. FEBS letters 27 10100865
2021 Gadd45g initiates embryonic stem cell differentiation and inhibits breast cell carcinogenesis. Cell death discovery 26 34601500
2016 Insight into Cr6+ reduction efficiency of Rhodococcus erythropolis isolated from coalmine waste water. Chemosphere 26 27728886
2012 Expression of cell growth negative regulators MEG3 and GADD45γ is lost in most sporadic human pituitary adenomas. Pituitary 25 21850407
2020 CR6 interacting factor 1 deficiency induces premature senescence via SIRT3 inhibition in endothelial cells. Free radical biology & medicine 24 32109515
2016 IL-27 attenuates airway inflammation in a mouse asthma model via the STAT1 and GADD45γ/p38 MAPK pathways. Journal of translational medicine 24 27687913
2009 Essential role of CR6-interacting factor 1 (Crif1) in E74-like factor 3 (ELF3)-mediated intestinal development. The Journal of biological chemistry 24 19801644
2020 Physiological, ultrastructural, biochemical, and molecular responses of glandless cotton to hexavalent chromium (Cr6+) exposure. Environmental pollution (Barking, Essex : 1987) 23 32829171
2010 Direct transcriptional induction of Gadd45gamma by Ascl1 during neuronal differentiation. Molecular and cellular neurosciences 23 20382226
2008 The crystal structure and dimerization interface of GADD45gamma. Proceedings of the National Academy of Sciences of the United States of America 23 18445651
2003 Gadd45gamma expression is reduced in anaplastic thyroid cancer and its reexpression results in apoptosis. The Journal of clinical endocrinology and metabolism 23 12915687
2000 Regulation of Gadd45gamma expression by C/EBP. European journal of biochemistry 23 11012671
2021 Downregulation of CR6-interacting factor 1 suppresses keloid fibroblast growth via the TGF-β/Smad signaling pathway. Scientific reports 22 33436666
2015 Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure. Diabetologia 22 25660120
2013 (-)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: role of topoisomerase IIα inhibition and reactive oxygen species. Toxicology 22 23313378
2005 Adenylyl cyclase activity and its modulation in the gills of Mytilus galloprovincialis exposed to Cr6+ and Cu2+. Aquatic toxicology (Amsterdam, Netherlands) 22 16242791
2019 Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 31826946
2016 Paired box 5 is a frequently methylated lung cancer tumour suppressor gene interfering β-catenin signalling and GADD45G expression. Journal of cellular and molecular medicine 21 26843424
2009 Participation of oxidative stress on rat middle cerebral artery changes induced by focal cerebral ischemia: beneficial effects of 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6). The Journal of pharmacology and experimental therapeutics 21 19692633
2006 The radical scavenger CR-6 protects SH-SY5Y neuroblastoma cells from oxidative stress-induced apoptosis: effect on survival pathways. Journal of neurochemistry 21 16787420
2020 Liraglutide improves atherosclerosis by regulating long non-coding RNA RMRP/miR-128-1-5P/Gadd45g axis. European review for medical and pharmacological sciences 20 32196624
2014 Comparative analysis of developmentally regulated expressions of Gadd45a, Gadd45b, and Gadd45g in the mouse and marmoset cerebral cortex. Neuroscience 20 25450958
2010 Semi-quantitative detection of GADD45-gamma methylation levels in gastric, colorectal and pancreatic cancers using methylation-sensitive high-resolution melting analysis. Journal of cancer research and clinical oncology 20 20111973
2010 GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells. Endocrinology 20 20739400
2007 CR6-interacting factor 1 represses the transactivation of androgen receptor by direct interaction. Molecular endocrinology (Baltimore, Md.) 20 17885209
2020 CR6-interacting factor 1 deficiency reduces endothelial nitric oxide synthase activity by inhibiting biosynthesis of tetrahydrobiopterin. Scientific reports 19 31964986
2015 Lymphocyte-specific protein tyrosine kinase (Lck) interacts with CR6-interacting factor 1 (CRIF1) in mitochondria to repress oxidative phosphorylation. BMC cancer 18 26210498
2013 Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression. Genes to cells : devoted to molecular & cellular mechanisms 17 23751077
1999 Prevention of glutamate neurotoxicity in cultured neurons by 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6), a scavenger of nitric oxide. Biochemical pharmacology 17 10423166
2022 Gadd45g, A Novel Antidepressant Target, Mediates Metformin-Induced Neuronal Differentiation of Neural Stem Cells Via DNA Demethylation. Stem cells (Dayton, Ohio) 16 35511865
2015 SIP1 is a downstream effector of GADD45G in senescence induction and growth inhibition of liver tumor cells. Oncotarget 16 26378039
2014 Neurogenin2-d4Venus and Gadd45g-d4Venus transgenic mice: visualizing mitotic and migratory behaviors of cells committed to the neuronal lineage in the developing mammalian brain. Development, growth & differentiation 16 24712911
2003 Comparative analysis of the genetic structure and chromosomal mapping of the murine Gadd45g/CR6 gene. DNA and cell biology 16 12932304
2020 MicroRNA-128-1-5p attenuates myocardial ischemia/reperfusion injury by suppressing Gadd45g-mediated apoptotic signaling. Biochemical and biophysical research communications 15 32828305
2008 Upregulation and function of GADD45gamma in unilateral ureteral obstruction. Kidney international 14 18354378
2006 Ascorbic acid differentially modulates the induction of heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase Ya by As(3+), Cd(2+) and Cr(6+). Cancer letters 14 16517059
2024 Adsorption of Hg2+/Cr6+ by metal-binding proteins heterologously expressed in Escherichia coli. BMC biotechnology 13 38521922
2023 Cr(VI)-bioremediation mechanism of a novel strain Bacillus paramycoides Cr6 with the powerful ability to remove Cr(VI) from contaminated water. Journal of hazardous materials 13 37207478
2019 GADD45G Interacts with E-cadherin to Suppress the Migration and Invasion of Esophageal Squamous Cell Carcinoma. Digestive diseases and sciences 12 31562612
2018 CR6 interacting factor 1 deficiency promotes endothelial inflammation by SIRT1 downregulation. PloS one 12 29474366
2014 Expression analysis of GADD45γ, MEG3, and p8 in pituitary adenomas. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 12 25126861
2004 Gadd45gamma is androgen-responsive and growth-inhibitory in prostate cancer cells. Molecular and cellular endocrinology 12 15062559
1999 Molecular cloning, expression, and mapping of a novel human cDNA, GRP17, highly homologous to human gadd45 and murine MyD118. Journal of human genetics 12 10496071
2020 Azacitidine regulates DNA methylation of GADD45γ in myelodysplastic syndromes. Journal of clinical laboratory analysis 11 33080073
2012 GADD45γ regulates TNF-α and IL-6 synthesis in THP-1 cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 11 22752116
2024 Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms. Nature communications 10 38582902
2014 GADD45γ induces G2/M arrest in human pharynx and nasopharyngeal carcinoma cells by cucurbitacin E. Scientific reports 10 25245461
2011 Carcinogenic heavy metals, As3+ and Cr6+, increase affinity of nuclear mono-ubiquitinated annexin A1 for DNA containing 8-oxo-guanosine, and promote translesion DNA synthesis. Toxicology and applied pharmacology 10 21315755
2020 Novel myocardial markers GADD45G and NDUFS5 identified by RNA-sequencing predicts left ventricular reverse remodeling in advanced non-ischemic heart failure: a retrospective cohort study. BMC cardiovascular disorders 9 32138671
2020 Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice. Neurobiology of aging 9 32711258
2015 Nuclear lymphocyte-specific protein tyrosine kinase and its interaction with CR6-interacting factor 1 promote the survival of human leukemic T cells. Oncology reports 9 25997448
2009 Fine temporal analysis of DHT transcriptional modulation of the ATM/Gadd45g signaling pathways in the mouse uterus. Molecular reproduction and development 9 18671277
2009 Urinary GADD45gamma expression is associated with progression of lgA nephropathy. American journal of nephrology 9 19293565
2009 Cytoprotection against Cr(6+)-induced DNA damage by alpha-lipoic acid: implications in reducing occupational cancer risk. Mutagenesis 9 19710206
2022 B Cell-Specific Deletion of CR6-Interacting Factor 1 Drives Lupus-like Autoimmunity by Activation of Interleukin-17, Interleukin-6, and Pathogenic Follicular Helper T Cells in a Mouse Model. Arthritis & rheumatology (Hoboken, N.J.) 8 35166061
2022 The GADD45G/p38 MAPK/CDC25B signaling pathway enhances neurite outgrowth by promoting microtubule polymerization. iScience 8 35497000

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