Affinage

GADD45B

Growth arrest and DNA damage-inducible protein GADD45 beta · UniProt O75293

Length
160 aa
Mass
17.8 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GADD45B is a stress-inducible nuclear signaling adaptor that integrates transcriptional inputs from inflammatory, growth-factor, and genotoxic stress pathways to regulate MAP kinase signaling, cell survival, and cell-cycle progression (PMID:11713530, PMID:12933797). It is transcriptionally induced as an immediate-early gene by NF-κB through RelA/p65 binding to multiple κB elements in its promoter (PMID:11713530, PMID:12162804), by TGF-β/Smad signaling through promoter and intronic enhancer elements (Smad2/3/4) (PMID:12933797, PMID:14630914), by p53 during anoxic stress via a p38α-p53 axis (PMID:23948959), and by activity-dependent neuronal signals downstream of c-Rel (PMID:26441517); nuclear receptors (CAR, PXR) and epitranscriptomic (FTO/m6A) and epigenetic mechanisms further tune its abundance (PMID:21965327, PMID:21127053, PMID:34513292). The protein's defining molecular activity is bidirectional MAP kinase control: it directly binds MKK7 and engages its ATP-binding site via helix α3 and loops 1–2 to impede catalysis, thereby suppressing pro-apoptotic JNK signaling and protecting cells from TNFα- and UV-induced death (PMID:11713530, PMID:17485467, PMID:16636063, PMID:29572137). Conversely, GADD45B binds and activates the MAPKKK MTK1/MEKK4 to stimulate p38 MAPK, an axis that drives TGF-β-induced hepatocyte apoptosis, T-cell IFNγ production, and chondrocyte and myogenic differentiation (PMID:12456654, PMID:12933797, PMID:15044949, PMID:20048163). Through MEKK4 it also directs p38 to autophagosomes, where p38 phosphorylates ATG5 at Thr75 to inhibit autophagy (PMID:23059785). GADD45B enforces cell-cycle checkpoints by binding and disrupting the CDK1/CyclinB1 complex to inhibit its kinase activity (PMID:12124778) and interacts with PCNA via its C-terminal region and with p21 to modulate DNA repair and growth control (PMID:8700517, PMID:10828065). In the nucleus it functions as a transcriptional coactivator of CAR at target gene regulatory elements (PMID:21965327) and mediates activity-induced DNA demethylation at the BDNF and FGF promoters to support adult hippocampal neurogenesis and memory (PMID:19119186, PMID:26441517). Additional effector roles include promoting G3BP1-dependent stress granule assembly and type I interferon signaling by dissolving G3BP1 autoinhibition (PMID:37917584) and promoting p53 degradation via a Src/PP2A/MDM2 pathway (PMID:23681232). The GADD45B/MKK7 interface is a validated cancer-cell-selective drug target: the peptide DTP3 disrupts this complex and kills multiple myeloma cells in vitro and in xenografts (PMID:25314077).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 Medium

    Established GADD45B (MyD118) as a nuclear protein with growth-control activity by identifying its first physical partners, framing it as a participant in DNA-damage/repair and cell-growth machinery.

    Evidence Immunofluorescence, co-IP with PCNA and p21, in vitro DNA repair and colony suppression assays

    PMID:8700517

    Open questions at the time
    • Interaction surfaces not mapped at this stage
    • Functional consequence of PCNA/p21 binding undefined
  2. 2000 High

    Mapped the GADD45B-PCNA interaction to defined domains and showed that PCNA binding restrains GADD45B growth suppression, revealing that partner engagement gates GADD45B function.

    Evidence Domain mapping, in vivo/in vitro interaction assays, colony formation with truncation constructs

    PMID:10828065

    Open questions at the time
    • Physiological context of PCNA-mediated restraint unclear
    • No structural model of the interaction
  3. 2001 High

    Placed GADD45B as the molecular link between NF-κB survival signaling and JNK antagonism, answering how NF-κB suppresses TNF-induced apoptosis.

    Evidence Genetic epistasis, antisense knockdown, reporter assays in cell lines

    PMID:11713530

    Open questions at the time
    • Direct JNK-pathway target not yet identified
    • Whether suppression is direct or via an intermediary unresolved at this point
  4. 2002 High

    Defined opposing MAP-kinase roles and a cell-cycle target: GADD45B activates p38 via MTK1/MEKK4 downstream of TGF-β, and inhibits CDK1/CyclinB1 by disrupting the complex for checkpoint control.

    Evidence Binding assays, antisense inhibition, reporter assays; in vitro kinase assay and co-IP with CDK1/CyclinB1; promoter dissection with EMSA defining κB elements

    PMID:12124778 PMID:12162804 PMID:12456654

    Open questions at the time
    • How GADD45B both activates p38 and inhibits JNK in the same cell unresolved
    • Structural basis of CDK1/CyclinB1 disruption unknown
  5. 2003 High

    Established GADD45B as a TGF-β/Smad immediate-early target driving p38-dependent apoptosis and G2 progression, linking a specific upstream pathway to defined cellular outcomes.

    Evidence Smad overexpression, intronic enhancer mapping, siRNA of individual Smads, Gadd45b-/- primary hepatocytes, reporter assays

    PMID:12933797 PMID:14630914

    Open questions at the time
    • Smad2 vs Smad3/4 requirement differs between reports
    • Cell-type basis for apoptotic vs proliferative outcome unclear
  6. 2004 High

    Confirmed MEKK4 as the obligate downstream mediator of GADD45B-driven p38 activation in T cells, cementing the GADD45B→MEKK4→p38 axis genetically.

    Evidence MEKK4-/- mice, T-cell stimulation, p38 activity and IFNγ readouts, genetic epistasis

    PMID:15044949

    Open questions at the time
    • Structural basis of MEKK4 activation by GADD45B not defined
  7. 2006 High

    Distinguished GADD45B from GADD45A in vivo by showing GADD45B specifically blocks the MKK4-JNK stress pathway to limit UV-induced apoptosis in hematopoietic cells.

    Evidence Gadd45a-/- and Gadd45b-/- bone marrow cells, UV irradiation, JNK/p38/NF-κB and apoptosis assays

    PMID:16636063

    Open questions at the time
    • Whether MKK4 inhibition is direct binding or indirect not established here
  8. 2007 High

    Provided residue-level mechanism for JNK suppression, showing GADD45B helices and loops dock MKK7 and engage its ATP-binding site to impede catalysis.

    Evidence Structural prediction, mutagenesis, binding and kinase activity assays

    PMID:17485467

    Open questions at the time
    • Prediction-based fold, not an experimental structure
    • Dynamics of conformational inhibition not directly observed
  9. 2008 High

    Demonstrated the physiological survival role of GADD45B-mediated JNK suppression in vivo, showing it sustains hepatocyte proliferation during liver regeneration.

    Evidence Gadd45b-/- mice, partial hepatectomy, epistasis with Jnk2-null rescue

    PMID:18382767

    Open questions at the time
    • Contribution of JNK1 vs JNK2 not fully dissected
  10. 2009 High

    Revealed a nuclear/epigenetic function distinct from MAPK signaling: GADD45B is required for activity-induced DNA demethylation at BDNF/FGF promoters driving adult hippocampal neurogenesis.

    Evidence Gadd45b knockout mice, bisulfite sequencing at defined loci, in vivo neurogenesis assays

    PMID:19119186

    Open questions at the time
    • Enzymatic basis of demethylation by GADD45B not defined
    • Whether GADD45B acts directly on DNA or recruits demethylation machinery unresolved
  11. 2010 High

    Expanded the mechanistic repertoire: GADD45B serves as a CAR-recruited JNK repressor, enhances p38-Rb interaction in Fas apoptosis, is induced via PXR, and drives chondrocyte Col10a1 transcription through MTK1/p38 and C/EBPβ.

    Evidence Knockout hepatocytes, co-IP, DR4 promoter reporters, siRNA, dominant-negative kinases, ChIP

    PMID:20048163 PMID:20404936 PMID:20558744 PMID:21127053

    Open questions at the time
    • How GADD45B selects between JNK-inhibitory and p38-activating outputs context-dependently unclear
    • Direct vs scaffold role in p38-Rb bridging not fully resolved
  12. 2011 High

    Defined GADD45B as a direct inducible transcriptional coactivator of nuclear receptor CAR at a target gene regulatory element, a nuclear function separable from its kinase modulation.

    Evidence Gadd45b-/- mice, ChIP at CYP2B10 element, interaction and domain mapping, reporter assays

    PMID:21965327

    Open questions at the time
    • Coactivator mechanism (co-recruited factors) not defined
    • Generality across other nuclear receptors unknown
  13. 2012 High

    Identified a regulatory link from GADD45B-MEKK4-p38 to autophagy, showing p38 phosphorylates ATG5-Thr75 to inhibit autophagosome maturation.

    Evidence Gadd45β-deficient and p38-deficient fibroblasts, autophagosome tracking, ATG5-Thr75 site identification, flux assays

    PMID:23059785

    Open questions at the time
    • Physiological settings where this axis dominates not mapped
    • How p38 is spatially targeted to autophagosomes mechanistically unclear
  14. 2013 Medium

    Added transcriptional regulators (p53 induction via p38α; STAT3 repression relieved by PPARα) and a JNK-independent anti-apoptotic route through p53 degradation, broadening GADD45B's stress-response circuitry.

    Evidence ChIP and SPR for p53-promoter binding; Stat3-null and Ppara-null mice, ubiquitination assays; Gadd45β-/- cells with p53 stability and pathway-inhibitor experiments

    PMID:23681232 PMID:23939942 PMID:23948959

    Open questions at the time
    • Mechanism by which GADD45B engages the Src/PP2A/MDM2 axis not structurally defined
    • Reconciliation of GADD45B as both p53 target and p53 destabilizer needs context
  15. 2014 High

    Validated the GADD45B/MKK7 complex as a druggable, cancer-cell-selective target by showing the peptide DTP3 disrupts it and kills multiple myeloma cells without normal-cell toxicity.

    Evidence Complex-disruption drug strategy, multiple myeloma cell lines, xenograft mouse models

    PMID:25314077

    Open questions at the time
    • Breadth of efficacy beyond multiple myeloma not established here
  16. 2018 High

    Refined the GADD45B-MKK7 interaction surface and DTP3 mechanism at residue level, mapping GADD45B loop 2 to the MKK7 enzymatic pocket.

    Evidence Enzymatic MS footprinting, diazirine cross-linking MS, MKK7 deletion-variant binding

    PMID:29572137

    Open questions at the time
    • No high-resolution co-crystal structure of the complex
  17. 2023 High

    Uncovered a non-kinase nuclear/cytoplasmic function: GADD45B dissolves G3BP1 autoinhibition to promote stress granule assembly and type I interferon signaling during RNA virus infection.

    Evidence Gadd45β KO mice, viral infection, co-IP with G3BP1, conformational and SG assembly assays, IFN readouts

    PMID:37917584

    Open questions at the time
    • Structural basis of G3BP1 conformational expansion not resolved
    • Relationship to GADD45B's MAPK roles in antiviral defense unclear
  18. 2024 Medium

    Extended GADD45B to disease tissue by showing dual p38-dependent and p38-independent (FOS-interacting) mechanisms driving airway inflammation and epithelial senescence in COPD.

    Evidence Gadd45b KO mice with cigarette-smoke exposure, bidirectional modulation in HBE cells, GADD45B-FOS interaction, promoter bisulfite sequencing

    PMID:38342401

    Open questions at the time
    • GADD45B-FOS interaction mechanism not structurally defined
    • Single-lab disease model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GADD45B selects among its many mutually opposing outputs (JNK inhibition vs p38 activation, apoptosis vs survival, autophagy inhibition, demethylation, stress-granule assembly) in a given cellular context remains unresolved.
  • No unifying model for context-dependent partner selection
  • No experimental high-resolution structure of GADD45B in complex with any partner
  • Enzymatic basis of GADD45B-facilitated DNA demethylation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-4839726 Chromatin organization 2 R-HSA-9612973 Autophagy 1
Partners
CCNB1CDK1CDKN1AG3BP1MEKK4MKK7NR1I3PCNA

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 GADD45B is transcriptionally upregulated by NF-κB (specifically RelA/p65) and directly suppresses TNF-induced JNK cascade activation, thereby protecting cells from TNFα-induced apoptosis. This establishes GADD45B as the molecular link between NF-κB and JNK pathway antagonism. Genetic epistasis, antisense inhibition, reporter assays, and loss-of-function in cell lines Nature High 11713530
2002 GADD45B (and GADD45G) specifically interact with the CDK1/CyclinB1 complex (but not other CDK/Cyclin complexes) in vitro and in vivo, inhibiting CDK1/CyclinB1 kinase activity; GADD45B inhibition involves disruption of the CDK1/CyclinB1 complex. All three GADD45 proteins cooperate in S and G2/M checkpoint activation after UV irradiation. In vitro kinase assay, co-immunoprecipitation, antisense RNA cell lines Journal of cellular physiology High 12124778
2002 GADD45B protein binds and activates MTK1 (MEKK4), a MAPKKK upstream of the p38 MAPK cascade, and Smad-dependent GADD45B expression is responsible for the delayed (but not early) TGF-β-induced p38 activation. Overexpression, antisense inhibition, binding assays, reporter assays in cell lines The EMBO journal High 12456654
2002 Three κB elements at positions -447/-438, -426/-417, and -377/-368 in the GADD45B promoter are each required for optimal transactivation; each site binds NF-κB complexes in vitro and RelA (but not Rel or p50) is sufficient to activate GADD45B expression. Promoter reporter assays, EMSA (electrophoretic mobility shift assay), transient transfection in HeLa cells DNA and cell biology Medium 12162804
2003 GADD45B expression is induced by TGF-β as an immediate-early response gene through Smad2, Smad3, and Smad4; ectopic GADD45B expression is sufficient to activate p38 and trigger apoptosis in hepatocytes; antisense inhibition of GADD45B blocks TGF-β-dependent p38 activation and apoptosis; Gadd45b-/- mouse primary hepatocytes fail to activate p38 or undergo apoptosis in response to TGF-β. Promoter reporter assay, Smad overexpression, ectopic expression, antisense knockdown, Gadd45b-/- primary hepatocytes The Journal of biological chemistry High 12933797
2003 A novel TGF-β-responsive enhancer in the third intron of the GADD45B gene mediates TGF-β induction; SMAD3 and SMAD4 (but not SMAD2) are required for this transcriptional activation. GADD45B-deficient cells arrest in G2 following TGF-β treatment, revealing a role for GADD45B in facilitating G2 progression. Genomic sequence alignment, siRNA knockdown of individual SMADs, reconstitution in SMAD-deficient cancer cells, reporter assays, loss-of-function cell lines The Journal of biological chemistry High 14630914
1996 GADD45B (MyD118) is a nuclear protein that interacts with PCNA and p21WAF1/CIP1; it modestly stimulates DNA repair in vitro; GADD45B, GADD45A, and p21 synergize in suppressing colony formation. Nuclear localization by immunofluorescence, co-immunoprecipitation, in vitro DNA repair assay, colony suppression assay Oncogene Medium 8700517
2000 The C-terminal region (amino acids 114–156) of GADD45B mediates interaction with PCNA; the N-terminal (1–46) and middle (100–127) regions of PCNA harbor the GADD45B-interacting domains. Ectopic expression of GADD45B N-terminal peptides lacking the PCNA-interacting domain suppresses colony formation and induces apoptosis more efficiently than full-length GADD45B, indicating PCNA interaction impedes GADD45B-mediated negative growth control. Complementary in vivo and in vitro interaction assays, domain mapping, colony formation assays The Journal of biological chemistry High 10828065
2007 GADD45B is a structured protein with a predicted four-stranded β-sheet core, five α-helices, and two acidic loops. Association with MKK7 is mediated by helices α3 and α4 and loops 1 and 2; α3 primarily mediates docking to MKK7, while loop 1 and α4-loop 2 engage the ATP-binding site to cause conformational changes that impede catalytic function. Structural prediction, mutagenesis, binding and kinase activity assays The Journal of biological chemistry High 17485467
2009 Neuronal activity induces GADD45B expression as an immediate-early gene in mature hippocampal neurons; GADD45B is required for activity-induced DNA demethylation of specific gene promoters (including BDNF and FGF) and for the resulting adult hippocampal neurogenesis. Gadd45b deletion causes specific deficits in activity-induced neural progenitor proliferation and dendritic growth. Gadd45b knockout mice, activity-induced neurogenesis assays, bisulfite sequencing for DNA methylation at specific promoters, in vivo hippocampal assays Science High 19119186
2006 In hematopoietic cells, GADD45B protects against UV-induced apoptosis by inhibiting the MKK4-JNK stress pathway (distinct from GADD45A, which activates a p38-NF-κB survival pathway). Gadd45b-deficient bone marrow cells show enhanced UV-induced apoptosis with increased JNK activation. Gadd45a- and Gadd45b-deficient mouse bone marrow cells, UV irradiation, JNK/p38/NF-κB signaling assays, apoptosis assays The Journal of biological chemistry High 16636063
2008 GADD45B promotes hepatocyte survival during liver regeneration by suppressing JNK activity; Gadd45b-/- mice show decreased hepatocyte proliferation, increased programmed cell death, and sustained JNK activation during liver regeneration. Imposing a Jnk2-null mutation completely rescues the regenerative defect in Gadd45b-/- mice (epistasis). Gadd45b-/- mice with partial hepatectomy model, epistasis with Jnk2-null mutation, JNK activation assays The Journal of clinical investigation High 18382767
2012 The GADD45β-MEKK4 pathway directs p38 specifically to autophagosomes, resulting in autophagosome accumulation through p38-mediated inhibition of lysosome fusion. p38 phosphorylates the autophagy regulator ATG5 at threonine 75, inhibiting starvation-induced autophagy. Gadd45β-deficient cells show increased autophagic flux. Gadd45β-deficient fibroblasts, p38-deficient fibroblasts, autophagosome tracking, identification of Atg5-Thr75 as phosphorylation site, autophagic flux assays Cell death and differentiation High 23059785
2014 GADD45β physically interacts with MKK7 to inhibit its kinase activity; disrupting the GADD45β/MKK7 complex with the D-tripeptide DTP3 kills multiple myeloma cells with cancer-cell specificity, without toxicity to normal cells. DTP3 ablates myeloma xenografts in mice. Drug-discovery strategy, disruption of GADD45β/MKK7 complex in cancer cells, in vitro and xenograft mouse models Cancer cell High 25314077
2011 GADD45β physically binds to nuclear receptor CAR (Constitutive Androstane Receptor) and functions as a direct transcriptional coactivator; GADD45β-CAR complex localizes to the CYP2B10 regulatory element upon TCPOBOP activation. Separate GADD45β domains mediate CAR binding and transcriptional activation. Gadd45b-/- mice show impaired early transcriptional stimulation of CAR target genes and growth delays after TCPOBOP. Gadd45b-/- mice, ChIP (chromatin immunoprecipitation), protein-protein interaction assays, domain mapping, transcriptional reporter assays The Journal of clinical investigation High 21965327
2010 GADD45B enhances Col10a1 transcription in chondrocytes via the MTK1/MKK3/MKK6/p38 signaling axis and activates the TAD4 domain of C/EBPβ; dominant-negative p38α (but not JNK) disrupts the combined effect of GADD45β and C/EBPβ on the Col10a1 promoter. GADD45β knockdown prevents p38 phosphorylation and decreases Col10a1 mRNA. Reporter assays, dominant-negative kinase constructs, siRNA knockdown, ChIP for C/EBPβ binding, kinase pathway dissection in chondrocytes The Journal of biological chemistry High 20048163
2010 CAR forms a protein complex with GADD45B; this complex represses MKK7-mediated phosphorylation of JNK1 and suppresses TNFα-induced cell death. The repression of JNK1 phosphorylation by TCPOBOP-activated CAR is abolished in Gadd45b-/- hepatocytes. In vitro protein-protein interaction assay, phosphorylation assay, primary hepatocytes from Car-/- and Gadd45b-/- mice, TNFα/actinomycin D cell death model PloS one High 20404936
2013 STAT3 acts as a transcriptional repressor of the GADD45B gene by binding to upstream regulatory elements; PPARα ligand (Wy-14,643) causes STAT3 ubiquitination and degradation (via ACOX1-induced H2O2/oxidative stress), relieving STAT3-mediated repression to activate GADD45B. Confirmed using liver-specific Stat3-null mice. Ppara-null and liver-specific Stat3-null mice, STAT3 ChIP, ubiquitination assay, forced ACOX1 overexpression, H2O2 treatment Hepatology High 23939942
2013 GADD45β promotes p53 protein degradation via the Src/PP2A/MDM2 pathway upon arsenite treatment, providing an anti-apoptotic effect independently of JNK inhibition. GADD45β-/- cells show elevated p53 upon arsenite exposure. GADD45β-/- cells, p53 protein stability assays, pathway inhibitors, epistasis experiments with JNK pathway Cell death & disease Medium 23681232
2004 GADD45β and GADD45γ act upstream of MEKK4 to activate p38 MAPK in T cells, promoting IFNγ production. CD4 T cells from MEKK4-/- mice have reduced p38 activity; GADD45β/γ-induced IFNγ production is abolished in MEKK4-/- T cells or with p38 inhibition, establishing MEKK4 as the obligate downstream mediator. MEKK4-/- mice, T cell stimulation, p38 activity assays, cytokine production measurement, genetic epistasis The EMBO journal High 15044949
2010 Pregnane X receptor (PXR) directly activates the GADD45β gene by binding to a distal direct repeat 4 (DR4) element in the GADD45β promoter; GADD45β expression then increases p38 MAPK phosphorylation, leading to morphological changes and cell migration in HepG2 cells. siRNA knockdown of GADD45β decreases PXR-induced p38 phosphorylation. Reporter assays with DR4 promoter element, siRNA knockdown, p38 phosphorylation assays, cell migration assays The Journal of biological chemistry Medium 21127053
2010 GADD45B enhances the interaction between p38 and retinoblastoma protein (Rb) during Fas-induced apoptosis in murine hepatocytes; depletion of GADD45B suppresses p38-mediated Rb phosphorylation and apoptosis without affecting p38 phosphorylation itself; ectopic GADD45B is sufficient to enhance p38-Rb interaction. siRNA knockdown, ectopic GADD45B expression, co-immunoprecipitation of p38-Rb, phospho-Rb and apoptosis assays in AML12 cells The Journal of biological chemistry Medium 20558744
2018 Chemical cross-linking mass spectrometry demonstrates that the interaction between GADD45β and MKK7 kinase domain largely occurs between GADD45β loop 2 (region 103–117) and the MKK7 kinase enzymatic pocket; DTP3 disrupts this interaction by contacting MKK7 peptides 113–136 and 259–274. Enzymatic MS footprinting, diazirine-based cross-linking mass spectrometry (CX-MS), MKK7 deletion variant binding assay International journal of biological macromolecules High 29572137
2016 GADD45B mediates podocyte injury through the ROS-GADD45B-p38 MAPK pathway; GADD45B inhibition of p38 is required for puromycin aminonucleoside (PAN)-induced podocyte apoptosis; ROS inhibition suppresses both GADD45B expression and subsequent p38 activation. Zebrafish podocyte-specific overexpression/morpholino knockdown, in vitro podocyte culture, GADD45B overexpression/shRNA knockdown, ROS inhibitor, p38 pathway assays Cell death & disease Medium 26794661
2016 Fasting-induced liver GADD45β controls fatty acid uptake through cytoplasmic retention of FABP1. Using liver/hepatocyte-specific gain- and loss-of-function strategies, GADD45β was shown to impact obesity-driven hyperglycaemia. Whole-body Gadd45b-/- mice, liver-specific overexpression and knockdown, FABP1 subcellular localization assays, metabolic measurements EMBO molecular medicine Medium 27137487
2023 GADD45β interacts with the RNA-binding domain of G3BP1, causing conformational expansion of G3BP1 by dissolving its autoinhibitory intramolecular interaction; this promotes G3BP1-mediated stress granule (SG) assembly and SG-dependent type I interferon signaling upon RNA virus infection. Gadd45β knockout mice have severely impaired SG formation and interferon production. Gadd45β KO mice, viral infection models, co-IP of Gadd45β-G3BP1, conformational assays, SG formation assays, interferon signaling readouts Cell reports High 37917584
2015 NF-κB c-Rel (but not p65/RelA) controls learning-induced GADD45β expression and associated BDNF DNA demethylation in hippocampal CA1 neurons during fear memory formation; conditional c-rel knockout and local siRNA knockdown prevent fear conditioning-induced increases in GADD45β mRNA, GADD45β binding at the BDNF gene, and BDNF DNA demethylation. c-rel KO mice, p65/RelA conditional mutants, pharmacological NF-κB inhibition, local siRNA knockdown in CA1, ChIP for GADD45β at BDNF promoter, bisulfite sequencing Frontiers in molecular neuroscience High 26441517
2013 GADD45β is transcriptionally induced by p53 via direct p53 binding to the GADD45β promoter during ischemia/anoxia; p38α-mediated phosphorylation of p53 at Ser15 and Ser20 is required for this induction, establishing a p38α-p53-GADD45β axis in anoxia-induced apoptosis. ChIP assay and surface plasmon resonance imaging for p53-promoter binding, p53 siRNA, p53 overexpression, p38α inhibitors, in vivo rat ischemia model Journal of molecular medicine High 23948959
2019 ALK5 (TGF-β receptor I) co-immunoprecipitates with GADD45B and mediates GADD45B protein levels by regulating Smad2/3 phosphorylation; ALK5 signaling promotes neural plasticity and neurological recovery after cerebral ischemia/reperfusion via GADD45B. Lentiviral knockdown/overexpression of ALK5 in vivo, co-immunoprecipitation of ALK5-GADD45B, Smad2/3 phosphorylation assays, neurological recovery measurement Cell death & disease Medium 31043581
2019 Gadd45b regulates GADD45β-mediated TGF-β signaling in colon epithelium by competitively binding to the N-terminal domain of Smad7, thereby inhibiting Smurf-mediated degradation of TGF-β receptor type 1 (TβRI) and sustaining TGF-β signaling for wound healing and epithelial restitution. Gadd45b-/- mice, DSS colitis model, bone marrow transplantation, protein interaction (competitive binding with Smad7 N-terminal domain), TβRI degradation assays Experimental & molecular medicine Medium 31666502
2024 GADD45B facilitates airway inflammation and epithelial cell senescence in COPD via two distinct mechanisms: (1) directly mediating p38 phosphorylation for inflammatory responses, and (2) interacting with FOS to promote cellular senescence in a p38 phosphorylation-independent manner. Gadd45b deficiency in CS-exposed mice alleviated inflammation and senescence. CS-induced GADD45B overexpression is partially mediated by DNA hypomethylation of the GADD45B promoter. Gadd45b KO mice with cigarette smoke exposure, bidirectional GADD45B modulation in HBE cells, p38 phosphorylation assays, GADD45B-FOS interaction studies, bisulfite sequencing of GADD45B promoter Journal of advanced research Medium 38342401
2021 FTO-mediated m6A demethylation increases GADD45B mRNA stability; FTO knockdown increases GADD45B m6A modification and decreases GADD45B mRNA stability. GADD45B drives myogenic differentiation by activating the p38 MAPK pathway, and inactivation of p38 abolishes GADD45B-mediated myogenesis. m6A profiling, FTO knockdown, GADD45B gain/loss-of-function in goat myoblasts, p38 MAPK inhibitor rescue Molecular therapy. Nucleic acids Medium 34513292

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science (New York, N.Y.) 723 19119186
2001 Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 655 11713530
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
2003 Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. The Journal of biological chemistry 221 12933797
1994 The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells. Molecular and cellular biology 192 8139540
1996 The differentiation primary response gene MyD118, related to GADD45, encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. Oncogene 156 8700517
2002 Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta. The EMBO journal 155 12456654
1991 Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines. Oncogene 136 1899477
1999 CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control. Oncogene 134 10490824
2006 Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. The Journal of biological chemistry 121 16636063
2003 Gadd45beta is important for perpetuating cognate and inflammatory signals in T cells. Nature immunology 120 14691480
2000 Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control. The Journal of biological chemistry 113 10828065
2012 Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. Cell death and differentiation 104 23059785
2005 Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis. Oncogene 100 16170381
2012 Genetic deletion of Gadd45b, a regulator of active DNA demethylation, enhances long-term memory and synaptic plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 23197699
2014 Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors. Cancer cell 95 25314077
2011 Identification of growth arrest and DNA-damage-inducible gene beta (GADD45beta) as a novel tumor suppressor in pituitary gonadotrope tumors. Endocrinology 93 21810943
2011 Growth arrest and DNA-damage-inducible, beta (GADD45b)-mediated DNA demethylation in major psychosis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 92 22048458
2004 GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. The EMBO journal 90 15044949
2008 Differential expression of GADD45beta in normal and osteoarthritic cartilage: potential role in homeostasis of articular chondrocytes. Arthritis and rheumatism 88 18576389
2005 Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia. Hepatology (Baltimore, Md.) 79 16231353
2008 Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. The Journal of clinical investigation 78 18382767
2010 Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells. Cancer research 72 21062976
2015 Metformin ameliorates acetaminophen hepatotoxicity via Gadd45β-dependent regulation of JNK signaling in mice. Journal of hepatology 71 25681557
2012 Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory. Learning & memory (Cold Spring Harbor, N.Y.) 65 22802593
2005 Co-activation of ERK, NF-kappaB, and GADD45beta in response to ionizing radiation. The Journal of biological chemistry 65 15642734
2016 Gadd45b prevents autophagy and apoptosis against rat cerebral neuron oxygen-glucose deprivation/reperfusion injury. Apoptosis : an international journal on programmed cell death 64 26882903
2002 Regulation of the gadd45beta promoter by NF-kappaB. DNA and cell biology 64 12162804
2021 FTO-mediated demethylation of GADD45B promotes myogenesis through the activation of p38 MAPK pathway. Molecular therapy. Nucleic acids 63 34513292
2007 Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. The Journal of biological chemistry 62 17485467
2010 Pregnane X receptor PXR activates the GADD45beta gene, eliciting the p38 MAPK signal and cell migration. The Journal of biological chemistry 61 21127053
2009 Gadd45b and Gadd45g are important for anti-tumor immune responses. European journal of immunology 61 19688743
2005 NF-kappaB and not the MAPK signaling pathway regulates GADD45beta expression during acute inflammation. The Journal of biological chemistry 61 15797874
2001 Ectopic expression of MyD118/Gadd45/CR6 (Gadd45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis. International journal of oncology 56 11251170
2016 A signaling cascade including ARID1A, GADD45B and DUSP1 induces apoptosis and affects the cell cycle of germ cell cancers after romidepsin treatment. Oncotarget 55 27572311
2012 Gadd45a and Gadd45b modulate innate immune functions of granulocytes and macrophages by differential regulation of p38 and JNK signaling. Journal of cellular physiology 55 22307729
2011 Gadd45β is an inducible coactivator of transcription that facilitates rapid liver growth in mice. The Journal of clinical investigation 55 21965327
2013 Hepatic oxidative stress activates the Gadd45b gene by way of degradation of the transcriptional repressor STAT3. Hepatology (Baltimore, Md.) 53 23939942
2019 ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b. Cell death & disease 52 31043581
2016 Sulforaphane, a Dietary Isothiocyanate, Induces G₂/M Arrest in Cervical Cancer Cells through CyclinB1 Downregulation and GADD45β/CDC2 Association. International journal of molecular sciences 51 27626412
2010 Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B. PloS one 51 20404936
2010 Downregulation of Gadd45beta expression by hepatitis C virus leads to defective cell cycle arrest. Cancer research 51 20530689
2019 TFAP2C increases cell proliferation by downregulating GADD45B and PMAIP1 in non-small cell lung cancer cells. Biological research 47 31296259
2006 Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation. Oncogene 47 16732331
2010 Gadd45b mediates Fas-induced apoptosis by enhancing the interaction between p38 and retinoblastoma tumor suppressor. The Journal of biological chemistry 46 20558744
2015 Gadd45b is a novel mediator of neuronal apoptosis in ischemic stroke. International journal of biological sciences 45 25678854
2010 Gadd45beta is a novel mediator of cardiomyocyte apoptosis induced by ischaemia/hypoxia. Cardiovascular research 45 20154065
2019 Gadd45b mediates depressive-like role through DNA demethylation. Scientific reports 44 30874581
2017 Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib. Cell death discovery 43 28900541
2016 GADD45B mediates podocyte injury in zebrafish by activating the ROS-GADD45B-p38 pathway. Cell death & disease 41 26794661
2015 NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation. Frontiers in molecular neuroscience 41 26441517
2003 Identification of a gadd45beta 3' enhancer that mediates SMAD3- and SMAD4-dependent transcriptional induction by transforming growth factor beta. The Journal of biological chemistry 41 14630914
1999 A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth. The Journal of biological chemistry 41 10455148
2018 Matrine inhibits the progression of prostate cancer by promoting expression of GADD45B. The Prostate 40 29356020
2015 Inhibition of microRNA-1 attenuates hypoxia/re-oxygenation-induced apoptosis of cardiomyocytes by directly targeting Bcl-2 but not GADD45Beta. American journal of translational research 40 26692938
2010 GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. The Journal of biological chemistry 40 20048163
2004 Transforming growth factor-beta (TGF-beta) type I receptor/ALK5-dependent activation of the GADD45beta gene mediates the induction of biglycan expression by TGF-beta. The Journal of biological chemistry 40 15546867
2020 Sulforaphene inhibits esophageal cancer progression via suppressing SCD and CDH3 expression, and activating the GADD45B-MAP2K3-p38-p53 feedback loop. Cell death & disease 39 32873775
2012 Abnormal expression of GADD45B in human colorectal carcinoma. Journal of translational medicine 39 23110778
2019 Endometrial mesenchymal stem cells isolated from menstrual blood repaired epirubicin-induced damage to human ovarian granulosa cells by inhibiting the expression of Gadd45b in cell cycle pathway. Stem cell research & therapy 38 30606243
2015 Sex-Specific Effects of Prenatal Stress on Bdnf Expression in Response to an Acute Challenge in Rats: a Role for Gadd45β. Molecular neurobiology 38 26676568
2011 Gadd45a, Gadd45b and Gadd45g expression during mouse embryonic development. Gene expression patterns : GEP 37 21843656
2019 Non-cell Autonomous OTX2 Homeoprotein Regulates Visual Cortex Plasticity Through Gadd45b/g. Cerebral cortex (New York, N.Y. : 1991) 36 29771284
2018 Triptolide attenuates proteinuria and podocyte apoptosis via inhibition of NF-κB/GADD45B. Scientific reports 36 30022148
2017 Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Target GADD45B To Protect Infected Cells from Cell Cycle Arrest and Apoptosis. Journal of virology 34 27852859
2017 GADD45β Loss Ablates Innate Immunosuppression in Cancer. Cancer research 34 29279355
2015 Gadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala. Brain, behavior, and immunity 34 25728234
2020 ALV-J inhibits autophagy through the GADD45β/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy. Cell death & disease 33 32826872
2009 Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling. Arthritis and rheumatism 33 19877043
2016 Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health. EMBO molecular medicine 32 27137487
2021 Fine particulate matter (PM2.5) promotes IgE-mediated mast cell activation through ROS/Gadd45b/JNK axis. Journal of dermatological science 31 33676788
2016 The protective role of Nrf2-Gadd45b against antimony-induced oxidative stress and apoptosis in HEK293 cells. Toxicology letters 29 27208483
2015 miR-146a and miR-370 coordinate enterovirus 71-induced cell apoptosis through targeting SOS1 and GADD45β. Cellular microbiology 29 25469565
2014 Gadd45b Mediates Axonal Plasticity and Subsequent Functional Recovery After Experimental Stroke in Rats. Molecular neurobiology 29 25324012
2020 Regulation of dopamine-dependent transcription and cocaine action by Gadd45b. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 28 32927466
2009 Reversing DNA methylation: new insights from neuronal activity-induced Gadd45b in adult neurogenesis. Science signaling 28 19336837
2019 Gadd45b Acts as Neuroprotective Effector in Global Ischemia-Induced Neuronal Death. International neurourology journal 27 30832463
1999 Post-transcriptional regulation of MyD118 and GADD45 in human lung carcinoma cells during 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2- naphthalene carboxylic acid-induced apoptosis. Molecular pharmacology 27 10101024
2009 Distinct mechanisms are utilized to induce stress sensor gadd45b by different stress stimuli. Journal of cellular biochemistry 26 19834918
2020 Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR). Acta pharmaceutica Sinica. B 24 33643822
2017 MicroRNA-206 Protects against Myocardial Ischaemia-Reperfusion Injury in Rats by Targeting Gadd45β. Molecules and cells 23 29237256
2011 Senescence of chondrocytes in aging articular cartilage: GADD45β mediates p21 expression in association with C/EBPβ in senescence-accelerated mice. Pathology, research and practice 23 21353395
2004 Zebrafish GADD45beta genes are involved in somite segmentation. Proceedings of the National Academy of Sciences of the United States of America 23 15623554
2024 DNA hypomethylation-mediated upregulation of GADD45B facilitates airway inflammation and epithelial cell senescence in COPD. Journal of advanced research 22 38342401
2016 Gadd45β ameliorates L-DOPA-induced dyskinesia in a Parkinson's disease mouse model. Neurobiology of disease 22 26875664
2013 Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury. Journal of molecular medicine (Berlin, Germany) 22 23948959
2021 Single-cell transcriptomics identifies Gadd45b as a regulator of herpesvirus-reactivating neurons. EMBO reports 21 34842321
2008 GADD45B inhibits MKK7-induced cardiac hypertrophy and the polymorphisms of GADD45B is associated with inter-ventricular septum hypertrophy. Biochemical and biophysical research communications 21 18515079
2021 Gadd45b mediates environmental enrichment-induced neurogenesis in the SVZ of rats following ischemia stroke via BDNF. Neuroscience letters 20 33421485
2018 Probing the interaction interface of the GADD45β/MKK7 and MKK7/DTP3 complexes by chemical cross-linking mass spectrometry. International journal of biological macromolecules 20 29572137
2018 GADD45β-I attenuates oxidative stress and apoptosis via Sirt3-mediated inhibition of ER stress in osteoarthritis chondrocytes. Chemico-biological interactions 20 30237062
2014 Comparative analysis of developmentally regulated expressions of Gadd45a, Gadd45b, and Gadd45g in the mouse and marmoset cerebral cortex. Neuroscience 20 25450958
2020 GADD45B Promotes Glucose-Induced Renal Tubular Epithelial-Mesenchymal Transition and Apoptosis via the p38 MAPK and JNK Signaling Pathways. Frontiers in physiology 19 33013461
2019 Menstrual blood derived mesenchymal stem cells combined with Bushen Tiaochong recipe improved chemotherapy-induced premature ovarian failure in mice by inhibiting GADD45b expression in the cell cycle pathway. Reproductive biology and endocrinology : RB&E 19 31311554
2015 Gadd45b and N-methyl-D-aspartate induced DNA demethylation in postmitotic neurons. Epigenomics 19 26111030
2013 GADD45β mediates p53 protein degradation via Src/PP2A/MDM2 pathway upon arsenite treatment. Cell death & disease 19 23681232
2008 Growth arrest and DNA damage protein 45b (Gadd45b) protects retinal ganglion cells from injuries. Neurobiology of disease 19 18977442
2023 Gadd45β is critical for regulation of type I interferon signaling by facilitating G3BP-mediated stress granule formation. Cell reports 18 37917584
2021 GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer. Frontiers in cell and developmental biology 18 34490266
2019 Gadd45β promotes regeneration after injury through TGFβ-dependent restitution in experimental colitis. Experimental & molecular medicine 18 31666502

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