Affinage

GADD45G

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

Length
159 aa
Mass
17.1 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GADD45G is a stress-inducible nuclear protein that functions as an obligate dimer to activate MAP3K4-dependent p38 MAPK and JNK signaling, thereby coupling diverse upstream signals to cell cycle arrest, apoptosis, differentiation, and inflammatory cytokine production. Structurally, GADD45G adopts an αβα sandwich fold and dimerizes via a conserved four-helix bundle interface that is essential for its growth-inhibitory and migration-suppressive activities; disruption of dimerization abolishes interaction with E-cadherin and CDK1/CyclinB1 inhibition (PMID:18445651, PMID:31562612, PMID:12124778). Through the GADD45G→MAP3K4→p38 axis, it phosphorylates GATA4 to drive SRY expression during male sex determination, activates ERRγ to induce UCP1-dependent thermogenesis in brown adipose tissue, instructs hematopoietic stem cell differentiation, and promotes cardiomyocyte apoptosis via RIP1/caspase-8 (PMID:23102581, PMID:25071184, PMID:25068120, PMID:26370247). Loss of Gadd45g in mice causes complete XY gonadal sex reversal, defective cold-induced thermogenesis, enhanced HSC self-renewal leading to myeloproliferative neoplasm-like disease, and impaired T-cell p38/JNK activation with loss of IFN-γ production (PMID:23516551, PMID:11371360, PMID:38582902).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 Medium

    Establishing GADD45G as a growth-suppressive gene: ectopic expression suppressed colony formation and was induced during neuronal cell death, placing it alongside GADD45A/B as a negative growth regulator.

    Evidence Colony formation assays in H1299 cells; overexpression in primary neurons and PC12 cells

    PMID:10100865 PMID:10490824

    Open questions at the time
    • No endogenous loss-of-function data at this point
    • Mechanism of growth suppression unknown
  2. 2000 High

    Identifying PCNA and p21 as physical interactors revealed that GADD45G shares the conserved PCNA/p21-binding domain with other family members, and that PCNA binding antagonizes its growth-inhibitory function.

    Evidence Co-immunoprecipitation, GST pull-down, domain mapping, cell-based growth assays

    PMID:11022036

    Open questions at the time
    • Functional consequence of p21 interaction not fully dissected
    • No structural basis for PCNA interaction
  3. 2001 High

    Knockout mice demonstrated that GADD45G is required for p38 and JNK activation in TH1 T cells, establishing its physiological role as an upstream activator of MAPK stress signaling and linking it to IFN-γ production and activation-induced cell death.

    Evidence Gadd45g−/− mice with kinase activation assays, cytokine measurements, contact hypersensitivity model

    PMID:11371360

    Open questions at the time
    • Direct biochemical mechanism of MAPK activation not identified
    • Whether GADD45G activates MAP3K4 directly or indirectly was unknown
  4. 2002 High

    Demonstrating that GADD45G specifically inhibits CDK1/CyclinB1 kinase activity without disrupting the complex resolved how it enforces G2/M arrest, distinguishing its mechanism from GADD45A/B which dissociate the CDK–cyclin complex.

    Evidence In vitro kinase assay, co-immunoprecipitation, antisense RNA cell lines

    PMID:12124778

    Open questions at the time
    • Structural basis for CDK1 inhibition without complex disruption unknown
    • In vivo cell-cycle arrest contribution relative to other family members unresolved
  5. 2004 High

    Genetic epistasis using MEKK4 (MAP3K4) knockout cells placed GADD45G upstream of MAP3K4→p38 in a defined linear signaling cascade, resolving the identity of the kinase through which GADD45G activates p38.

    Evidence MEKK4−/− T cells, p38 inhibitor, epistasis with double KO, IFN-γ readout

    PMID:15044949

    Open questions at the time
    • Whether GADD45G binds MAP3K4 directly or through an adaptor was not resolved
    • Tissue generality of the GADD45G→MAP3K4 axis not established
  6. 2008 High

    The crystal structure revealed the αβα sandwich fold and a four-helix bundle dimer interface; mutagenesis proved dimerization is obligate for growth inhibition, providing the first structural framework for all GADD45 family functions.

    Evidence X-ray crystallography at atomic resolution, site-directed mutagenesis, colony-formation assays

    PMID:18445651

    Open questions at the time
    • No co-crystal with any binding partner (MAP3K4, CDK1, PCNA)
    • How dimerization enables downstream signaling mechanistically unresolved
  7. 2012 High

    Two independent studies demonstrated that Gadd45g knockout causes complete XY sex reversal by failing to activate the p38→GATA4→SRY transcriptional cascade, revealing a critical developmental role and genetic interaction with Map3k4.

    Evidence Gadd45g−/− and Map3k4−/− mice, transgenic Map3k4 rescue, GATA4 ChIP on Sry promoter, p38 phosphorylation assays

    PMID:23102580 PMID:23102581 PMID:23516551

    Open questions at the time
    • Upstream signal that induces Gadd45g in the gonad at 11.5 dpc not identified
    • Whether human GADD45G variants cause disorders of sex development remains uncharacterized
  8. 2014 High

    Three studies expanded the GADD45G→MAP3K4→p38 axis to new biological contexts: cold-induced thermogenesis in brown fat (via ERRγ/UCP1) and hematopoietic stem cell differentiation (overriding self-renewal), demonstrating broad tissue utilization of the same core signaling module.

    Evidence Gadd45g−/− mice under cold exposure, genome-wide cDNA screen for ERR activity; single-cell videomicroscopy of LT-HSCs with gain/loss-of-function

    PMID:25068120 PMID:25071184

    Open questions at the time
    • How tissue-specific upstream regulators selectively induce GADD45G in BAT vs. HSCs not resolved
    • Relative contributions of p38 vs. JNK in HSC differentiation not separated
  9. 2015 High

    GADD45G was shown to promote cardiomyocyte apoptosis via p38-dependent activation of RIP1 and caspase-8, and separately to induce tumor cell senescence via JNK→SIP1, demonstrating context-dependent engagement of distinct downstream effectors.

    Evidence AAV9 overexpression and Gadd45g−/− mice in myocardial infarction model; JNK inhibitor and SIP1 knockdown in xenograft tumor model

    PMID:26370247 PMID:26378039

    Open questions at the time
    • How the same p38/JNK activation leads to apoptosis in cardiomyocytes vs. senescence in tumor cells is not mechanistically explained
    • Direct interaction between GADD45G and RIP1 not demonstrated
  10. 2019 Medium

    GADD45G was found to physically interact with E-cadherin in a dimerization-dependent manner to suppress cancer cell migration, and hippocampal knockdown showed that the p38/JNK axis regulates synaptic plasticity genes and memory, broadening its functional repertoire beyond cell cycle control.

    Evidence GST pull-down and co-IP with dimer-dissociating mutant in ESCC cells; in vivo hippocampal knockdown with kinase/behavioral readouts

    PMID:31562612 PMID:31826946

    Open questions at the time
    • E-cadherin binding domain on GADD45G not mapped
    • Whether memory deficits are cell-autonomous to neurons not established
    • Single-lab findings for both observations
  11. 2022 Medium

    GADD45G was linked to active DNA demethylation at the NeuroD1 promoter during neuronal differentiation, with Gadd45g−/− mice showing impaired hippocampal neurogenesis and cognitive deficits, adding an epigenetic effector mechanism.

    Evidence Gadd45g−/− mice, NSC differentiation, NeuroD1 promoter bisulfite sequencing, behavioral tests

    PMID:35511865

    Open questions at the time
    • Whether GADD45G recruits TET enzymes or other demethylation machinery directly is not established
    • Single-lab study
  12. 2024 High

    GADD45G insufficiency was shown to drive myeloproliferative neoplasm through activation of RAC2→PAK1→PI3K-AKT signaling, revealing a p38-independent oncosuppressive mechanism and disease-relevant pathway in hematopoiesis.

    Evidence Gadd45g knockout/knockdown in hematopoietic system, RAC2/PAK1/PI3K-AKT pathway assays, MPN phenotyping

    PMID:38582902

    Open questions at the time
    • Whether GADD45G directly inhibits RAC2 or acts indirectly not resolved
    • Relationship between RAC2/PAK1/AKT axis and the known MAP3K4/p38 axis not clarified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of GADD45G dimer interactions with MAP3K4, CDK1, and E-cadherin; the mechanism by which GADD45G promotes DNA demethylation; whether human GADD45G mutations cause disorders of sex development or hematologic disease; and how cell-type context determines whether GADD45G activation leads to apoptosis, senescence, differentiation, or cell-cycle arrest.
  • No co-crystal structure with any partner
  • No human genetic disease formally linked to GADD45G mutations
  • Context-dependent outcome selection mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CDH1CDK1CDKN1ACRIF1GATA4MAP3K4PCNA

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) in vitro and in vivo, inhibiting its kinase activity. Unlike GADD45A and GADD45B, GADD45G inhibits CDK1/CyclinB1 without disrupting the complex. All three GADD45 proteins cooperate in S and G2/M checkpoint activation following UV irradiation. In vitro binding assay, co-immunoprecipitation, kinase activity assay, antisense RNA cell lines Journal of cellular physiology High 12124778
2001 GADD45G mediates activation of the p38 and JNK MAP kinase pathways in TH1 effector T cells downstream of TCR signaling, and is required for IFN-gamma production and activation-induced cell death (AICD). Gadd45g-/- TH1 cells are severely compromised in p38 and JNK activation upon restimulation. Gadd45gamma knockout mice, kinase activation assays, cytokine production assays, contact hypersensitivity model Immunity High 11371360
2000 GADD45G (CR6) interacts with PCNA and p21 via a conserved domain also used by GADD45A and GADD45B. Interaction with PCNA impedes GADD45G's function in negative growth control. Co-immunoprecipitation, GST pull-down, domain mapping, cell-based growth assays The Journal of biological chemistry High 11022036
2004 GADD45G and GADD45B act through MEKK4 (MAP3K4) to activate p38 and promote IFN-gamma production in CD4 T cells. Expression of GADD45B or GADD45G promotes IFN-gamma production in MEKK4+/+ but not MEKK4-/- cells or cells treated with a p38 inhibitor, placing GADD45G upstream of MEKK4 and p38 in this pathway. MEKK4 knockout mice, epistasis analysis, p38 activity assays, cytokine production assays The EMBO journal High 15044949
2008 Crystal structure of GADD45G reveals an alphabetaalpha sandwich fold with a central five-stranded mixed beta-sheet. GADD45G forms dimers via a four-helix bundle interface comprising the most conserved residues among GADD45 isoforms. Point mutations that disrupt dimerization while preserving monomer structure abolish growth inhibitory activity, demonstrating that dimerization is essential for function. X-ray crystallography, site-directed mutagenesis, cell-based growth inhibition assays Proceedings of the National Academy of Sciences of the United States of America High 18445651
2012 GADD45G is required for male sex determination: mice lacking Gadd45g exhibit complete XY gonadal sex reversal due to reduced/delayed Sry expression. The mechanism involves GADD45G activating p38 MAPK signaling, which promotes phosphorylation of GATA4, enabling GATA4 to bind the Sry promoter and drive Sry expression (GADD45G → p38 MAPK → GATA4 → SRY). Gadd45g knockout mice, p38 phosphorylation assays, GATA4 chromatin immunoprecipitation, promoter demethylation analysis Developmental cell High 23102580 23102581
2012 Gadd45g and Map3k4 genetically interact during gonadal sex determination. Transgenic overexpression of Map3k4 rescues gonadal defects in Gadd45g-deficient embryos. Sex reversal in both mutants is associated with reduced phosphorylation of p38 MAPK and GATA4, and p38alpha/p38beta double knockout embryos also show XY sex reversal. Gadd45g and Map3k4 knockout mice, transgenic rescue, p38 and GATA4 phosphorylation assays Developmental cell High 23102580
1999 Ectopic expression of GADD45G (CR6) suppresses colony formation of human lung carcinoma H1299 cells, demonstrating a role in negative growth control consistent with family members GADD45A and GADD45B. Colony formation assay, ectopic expression in H1299 cells Oncogene Medium 10490824
2003 CRIF1 (CR6-interacting factor 1) physically interacts with GADD45G (CR6/Gadd45gamma) as well as GADD45A and GADD45B. CRIF1 co-localizes with GADD45G in the nucleus. Recombinant CRIF1 inhibits CDK1/CyclinB1 and CDK2/CyclinE kinase activities with additive effects when combined with GADD45 proteins. GST pull-down, mammalian two-hybrid, co-immunoprecipitation, co-localization, in vitro kinase assay The Journal of biological chemistry High 12716909
2001 Inducible ectopic expression of GADD45G in M1 myeloblastic leukemia and H1299 lung carcinoma cell lines causes G1 accumulation and sensitizes cells to genotoxic-stress-induced apoptosis (UV, MMS, gamma-irradiation, VP16), without activating the MTK1/JNK/p38 stress cascade in the absence of extrinsic stress. IPTG-inducible expression system, flow cytometry cell cycle analysis, apoptosis assays, kinase pathway analysis International journal of oncology Medium 11251170
2014 GADD45G is a cold-induced activator of UCP1 and oxidative capacity in brown adipose tissue (BAT). Gadd45g knockout mice show defects in Ucp1 induction and thermogenic response to cold. GADD45G works by activating p38 MAPK, which activates ERRbeta and ERRgamma transcriptional function independently of PGC-1 coactivators, yet synergizes with PGC-1alpha in the thermogenic program. Gadd45g knockout mice, cold exposure, UCP1 expression assays, genome-wide cDNA screen for ERR activity, p38 activity 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) and overrides self-renewal by specifically activating MAP3K4-mediated MAPK p38. Absence of GADD45G enhances LT-HSC self-renewal potential. GADD45G expression causes selective lineage choice with reduction in megakaryocytic-erythroid cells within 36 hr. Videomicroscopy single-cell tracking, GADD45G overexpression/knockout in LT-HSCs, MAP3K4 pathway analysis, differentiation assays Stem cell reports High 25068120
2015 GADD45G overexpression in cardiomyocytes induces apoptosis, fibrosis, left ventricular dysfunction, and heart failure. Genetic deletion of Gadd45g confers resistance to ischemic injury by limiting cardiomyocyte apoptosis. Mechanistically, GADD45G activates receptor-interacting protein 1 (RIP1) and caspase-8 in a p38 MAPK-dependent manner to promote cardiomyocyte death. AAV9-mediated overexpression, Gadd45g knockout mice, myocardial infarction model, RIP1/caspase-8 activation assays, p38 inhibition Cardiovascular research High 26370247
2013 In Gadd45g-deficient XY mice on C57BL/6 background, all XY mice are born as completely sex-reversed XY-females. The molecular cause is failure to achieve the SRY expression threshold necessary for testis differentiation. Gadd45g expression peaks at ~11.5 dpc in both male and female embryonic gonads at the time of sex differentiation. Gadd45g knockout mice on defined genetic backgrounds, RT-PCR, histology, SRY expression analysis PloS one High 23516551
2001 Gadd45gamma expression in peripheral T cells is induced by IL-2 through a signaling pathway mediated by the tyrosine kinase Jak3 and transcription factors Stat5a and Stat5b. Gadd45gamma knockout mice, gene expression analysis, Jak3/Stat5 pathway dissection Molecular and cellular biology Medium 11287618
1999 GADD45G mRNA is induced during neuronal cell death caused by neurotrophic factor deprivation and Ca2+ ionophore treatment in PC12 cells. Overexpression of GADD45G in superior cervical ganglion neurons causes cell death. Rat GADD45G cloning, northern blot, ectopic overexpression in primary neurons FEBS letters Medium 10100865
2000 C/EBP family proteins (C/EBPbeta and C/EBPdelta) regulate transcriptional activity of the GADD45G promoter through a non-canonical C/EBP-binding site. C/EBP binding and GADD45G induction are coordinated during IL-6-induced M1 cell differentiation. Promoter cloning, EMSA, reporter gene analysis, expression profiling during differentiation European journal of biochemistry Medium 11012671
2013 SIRT1 activation reduces binding of NF-kappaB/STAT3 complexes to the GADD45G promoter, leading to GADD45G upregulation. STAT3 acts as a co-repressor with NF-kappaB at the GADD45G promoter. This was demonstrated by ChIP assays and EMSA showing NF-kappaB binds directly and STAT3 binds indirectly in complexes with NF-kappaB. ChIP assays, EMSA, siRNA knockdown, promoter reporter assays Cell death & disease Medium 23681230
2010 The basic helix-loop-helix transcription factor Ascl1 directly transcriptionally induces Gadd45g during neuronal differentiation. Two E-box consensus sites within the Gadd45g promoter are necessary for Ascl1 regulation, and Ascl1 is bound to this region in vivo. Overexpression of Gadd45g alone is sufficient to initiate some aspects of neuronal differentiation. Chromatin immunoprecipitation, transactivation assays, E-box mutagenesis, doxycycline-inducible Ascl1 expression, overexpression differentiation assays Molecular and cellular neurosciences High 20382226
2014 miR-383 directly targets the 3'-UTR of GADD45G mRNA, reducing its expression. Forced miR-383 expression increased cellular sensitivity to DNA damage in breast cancer cells, an effect rescued by ectopic GADD45G expression lacking the 3'-UTR. miR-383 also negatively regulates Gadd45g in embryonic stem cells and inhibits ES cell differentiation via Gadd45g targeting. 3'-UTR luciferase reporter assay, miR-383 overexpression/inhibition, rescue experiments with 3'-UTR-deleted GADD45G PloS one Medium 25415264
2015 GADD45G induces tumor cell senescence through JNK-mediated transcriptional activation of SIP1 (Smad-interacting protein 1). JNK inhibition counteracts GADD45G-induced senescence. Knockdown of SIP1 abrogates the suppressive effects of GADD45G on xenografted liver tumor growth in vivo. GADD45G overexpression, SIP1 knockdown, JNK inhibitor, xenograft tumor model, in vivo growth assays Oncotarget Medium 26378039
2008 GADD45G activates p38 MAPK and JNK signaling pathways to induce G2/M arrest in HepG2 hepatoma cells. G2/M arrest induced by GADD45G overexpression involves activation of both p38 and JNK kinase pathways. Transient transfection, flow cytometry, p38 and JNK kinase pathway analysis Molecular biology reports Medium 19048389
2013 Gadd45g regulates dental epithelial cell proliferation during tooth development via p38 MAPK-mediated induction of p21. Gadd45g is expressed in enamel knots and inhibits proliferation of dental epithelial cells through the p38/p21 axis. In situ expression analysis, Gadd45g overexpression, p21 reporter assays, p38 inhibition, proliferation assays Genes to cells Medium 23751077
2019 GADD45G interacts physically with E-cadherin (detected by GST pull-down and co-immunoprecipitation) and enhances E-cadherin membrane localization. This interaction suppresses esophageal squamous cell carcinoma cell migration and invasion. A dimer-dissociating GADD45G mutant loses the ability to interact with E-cadherin and fails to suppress migration/invasion, linking dimerization to this function. GST pull-down, co-immunoprecipitation, subcellular fractionation, Transwell migration/invasion assays, dimer-dissociating mutant Digestive diseases and sciences Medium 31562612
2019 Gadd45g reduction in the hippocampus impairs activity of p38 MAPK and JNK, disrupts activation of downstream targets ATF-2, c-Jun, and CREB, and reduces induction of early- and late-response genes associated with synaptic plasticity and aging. Mimicking age-associated Gadd45g decrease in young mice leads to age-like hippocampus-dependent memory deficits. Gadd45g knockdown in hippocampus, p38/JNK activity assays, downstream transcription factor activation, behavioral memory tests The Journal of neuroscience Medium 31826946
2021 GADD45G upregulation in AML impairs homologous recombination DNA repair, leading to DNA damage accumulation, apoptosis, differentiation, growth arrest, and increased sensitivity to chemotherapy. GADD45G is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9. GADD45G overexpression in AML cells, homologous recombination repair assays, DNA damage markers, apoptosis assays, HDAC inhibitor treatment Blood Medium 33945602
2024 GADD45G insufficiency drives myeloproliferative neoplasm pathogenesis. The pathogenic mechanism of GADD45G insufficiency is mediated through activation of RAC2, PAK1, and PI3K-AKT signaling pathways. Gadd45g insufficiency in the murine hematopoietic system alone leads to enhanced myeloid-biased HSC self-renewal and MPN-like phenotypes. Gadd45g knockout/knockdown mice, pathway activation assays (RAC2, PAK1, PI3K-AKT), hematopoietic stem cell assays Nature communications High 38582902
2022 Gadd45g mediates metformin-induced neuronal differentiation of neural stem cells via DNA demethylation of the neurogenic differentiation 1 (NeuroD1) promoter. Gadd45g increases demethylation through regulation of passive and active DNA demethylation enzymes via an AMPK-independent mechanism. Gadd45g-deficient mice show decreased hippocampal neurogenesis, spatial memory decline, and depression-like behaviors. Gadd45g knockout mice, NSC differentiation assays, NeuroD1 promoter methylation analysis, behavioral tests, AMPK inhibitor Stem cells Medium 35511865
2014 GADD45G activates MAPK signaling in hematopoietic stem cells by increasing expression of positive modulators including Csf1r, Igf2, and Fgfr3. Inhibition of MAPK signaling with a MEK inhibitor eliminates the differentiation phenotype caused by Gadd45g upregulation in embryonic stem cells. Gadd45g overexpression in ESCs, gene expression analysis, MEK inhibitor rescue, proliferation assays Cell death discovery Medium 34601500
2012 GADD45G regulates TNF-alpha and IL-6 production in LPS-stimulated THP-1 monocyte cells. GADD45G knockdown reduces TNF-alpha protein by 75% and IL-6 by 60%, while overexpression dramatically increases both. JNK acts as a downstream mediator of the pro-inflammatory effects of GADD45G. Lentiviral shRNA knockdown, GADD45G overexpression, JNK inhibitor (SP600125), ELISA protein quantification Inflammation research Medium 22752116

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 179 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 86 11022036
2017 The Ca2+ /calmodulin2-binding transcription factor TGA3 elevates LCD expression and H2 S production to bolster Cr6+ tolerance in Arabidopsis. The Plant journal : for cell and molecular biology 82 28670772
2003 CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle. The Journal of biological chemistry 79 12716909
2004 Loss of expression of the growth inhibitory gene GADD45gamma, in human pituitary adenomas, is associated with CpG island methylation. Oncogene 73 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
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
2005 The role of oxidative stress in the modulation of aryl hydrocarbon receptor-regulated genes by As3+, Cd2+, and Cr6+. Free radical biology & medicine 61 16274885
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 46 26370247
2014 GADD45γ regulates the thermogenic capacity of brown adipose tissue. Proceedings of the National Academy of Sciences of the United States of America 43 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
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
2020 Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6. Journal of medicinal chemistry 31 32706255
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
2021 GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML. Blood 29 33945602
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
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
2016 IL-27 attenuates airway inflammation in a mouse asthma model via the STAT1 and GADD45γ/p38 MAPK pathways. Journal of translational medicine 23 27687913
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
2020 CR6 interacting factor 1 deficiency induces premature senescence via SIRT3 inhibition in endothelial cells. Free radical biology & medicine 22 32109515
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
2021 Downregulation of CR6-interacting factor 1 suppresses keloid fibroblast growth via the TGF-β/Smad signaling pathway. Scientific reports 20 33436666
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
2020 Liraglutide improves atherosclerosis by regulating long non-coding RNA RMRP/miR-128-1-5P/Gadd45g axis. European review for medical and pharmacological sciences 19 32196624
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
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
2024 Adsorption of Hg2+/Cr6+ by metal-binding proteins heterologously expressed in Escherichia coli. BMC biotechnology 12 38521922
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
2019 GADD45G Interacts with E-cadherin to Suppress the Migration and Invasion of Esophageal Squamous Cell Carcinoma. Digestive diseases and sciences 11 31562612
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
2020 Azacitidine regulates DNA methylation of GADD45γ in myelodysplastic syndromes. Journal of clinical laboratory analysis 10 33080073
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
2024 Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms. Nature communications 9 38582902
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