Affinage

JUN

Transcription factor Jun · UniProt P05412

Length
331 aa
Mass
35.7 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

c-Jun is a bZIP transcription factor that binds AP-1 DNA elements as a homodimer or, with ~25-fold higher affinity, as a heterodimer with c-Fos, providing the combinatorial basis for AP-1 target selection (PMID:3142692). Its transactivation is switched on by N-terminal phosphorylation of two serines (Ser63/Ser73) in the transactivation domain: MAP kinases respond to mitogens, phorbol esters, and Ras (PMID:1922387), while a dedicated subfamily of stress-activated kinases (SAPK/JNK) responds to cellular stress and TNF-α and docks on c-Jun's delta-region and an auxiliary site in the DNA-binding domain (PMID:8177321, PMID:9837920). DNA binding is reciprocally controlled by the phosphorylation state of a C-terminal Thr/Ser cluster, coupling intramolecular signal transduction to activity (PMID:7744008). c-Jun protein levels are set by competing post-translational inputs: multi-ubiquitination targets it for degradation (a determinant residing in the N-terminal delta-domain), SUMO-1 conjugation at Lys229 dampens activity in a manner relieved by JNK phosphorylation, and stability is further tuned by the deubiquitinase USP6, the FBW7/PRR7 axis, O-GlcNAcylation at Ser73, and intracellular lactate sensing (PMID:8922589, PMID:10788439, PMID:29061731, PMID:27458189, PMID:31394193, PMID:35263597). Through these activities c-Jun drives proliferation and survival by directly repressing the p53 and PTEN promoters and activating cyclin D1, and it is an essential effector of Ras-induced transformation (PMID:10072388, PMID:16676006, PMID:9878062, PMID:8754851). Genetically, c-Jun is required for fetal hepatogenesis, hepatocyte survival, and cardiac outflow tract development (PMID:8371760, PMID:10352021), for keratinocyte wound healing via an HB-EGF/EGFR autocrine loop (PMID:12791271, PMID:12791272), for joint specification through direct control of Wnt9a/Wnt16 (PMID:23475960), and for Schwann cell dedifferentiation and the repair program of Wallerian degeneration, where it activates GDNF and Artemin to support axonal regeneration (PMID:18490512, PMID:22920255, PMID:22753894). c-Jun additionally modulates transcriptional programs through direct protein interactions with nuclear receptors (GR, AR), MyoD, Rb, ATF2, Ski, and the chromatin modifier KDM4B (PMID:2169353, PMID:8798722, PMID:1310896, PMID:9545246, PMID:16511568, PMID:12034730, PMID:30683841), and has a non-transcriptional nucleolar role in rRNA processing via interaction with DDX21 (PMID:18180292).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1988 High

    Established the molecular basis of AP-1 DNA recognition by defining c-Jun's homo- versus heterodimeric binding modes.

    Evidence In vitro translation with gel retardation and co-translation dimerization assays

    PMID:3142692

    Open questions at the time
    • Did not address in vivo target selection
    • No structural detail on the dimer interface beyond the leucine zipper requirement
  2. 1990 High

    Showed c-Jun activity is integrated with nuclear receptor signaling through DNA-binding-independent mutual repression with the glucocorticoid receptor.

    Evidence Reporter assays, mutant analysis, and gel retardation with bacterially expressed proteins

    PMID:2169353

    Open questions at the time
    • Did not resolve whether repression is via direct contact or competition for cofactors
    • Physiological contexts of crosstalk not defined
  3. 1991 High

    Identified the activating N-terminal serine phosphorylation that links mitogen/Ras signaling to c-Jun transactivation, and a parallel protein-interaction repression of MyoD-driven myogenesis.

    Evidence In vitro kinase assays with site mapping, reporter assays, and co-IP/in vitro binding with mutagenesis

    PMID:1310896 PMID:1922387

    Open questions at the time
    • The principal physiological N-terminal kinase was not yet identified
    • Mechanism of MyoD repression downstream of binding not fully defined
  4. 1994 High

    Defined the JNK/SAPK pathway as the dedicated stress/TNF-α route to c-Jun, distinguishing it from mitogen-activated ERKs.

    Evidence Molecular cloning with in vitro kinase substrate specificity profiling and cell stimulation

    PMID:8177321

    Open questions at the time
    • Upstream kinase cascade not fully mapped
    • Substrate scope beyond c-Jun not delineated here
  5. 1995 Medium

    Revealed intramolecular regulation: C-terminal dephosphorylation activates DNA binding as an indirect consequence of N-terminal phosphorylation.

    Evidence Phosphorylation-site mutagenesis with DNA-binding assays under phorbol ester stimulation

    PMID:7744008

    Open questions at the time
    • Phosphatase responsible for C-terminal dephosphorylation not identified
    • Single-lab mechanistic inference
  6. 1996 High

    Placed c-Jun as an essential effector of Ras transformation and clarified its differential turnover relative to JunD.

    Evidence c-jun null fibroblast transformation assays with rescue; in vivo ubiquitination and pulse-chase with delta-domain mutants; modified two-hybrid for AR interaction

    PMID:8754851 PMID:8798722 PMID:8922589

    Open questions at the time
    • E3 ligase responsible for c-Jun ubiquitination not identified at this stage
    • AR interaction shown by a single interaction method
  7. 1998 High

    Mapped JNK docking on c-Jun and identified Rb and the ERK pathway as positive regulators of c-Jun-dependent transcription and neuronal differentiation.

    Evidence Reciprocal co-IP and in vitro binding with purified proteins; cell-cycle synchronized co-IP/reporter; PC12 gain/loss-of-function differentiation assays

    PMID:9545246 PMID:9687508 PMID:9837920

    Open questions at the time
    • Functional consequence of the auxiliary JNK-binding site uncertain
    • Rb activation of c-Jun studied in limited cell types
  8. 1999 High

    Defined the core proliferative/survival outputs of c-Jun: cyclin D1 activation, direct p53 promoter repression as the rate-limiting proliferation function, and anti-apoptotic protection.

    Evidence c-jun null fibroblasts, promoter-reporter assays, AP-1 site mutagenesis, S63A/S73A mutants, and p53 knockout epistasis; fetal liver knockout phenotyping with hematopoietic reconstitution

    PMID:10072388 PMID:10352021 PMID:9878062

    Open questions at the time
    • Phosphorylation-independent cyclin D1 control mechanism not fully resolved
    • Tissue specificity of p53 repression not broadly tested
  9. 2000 High

    Identified SUMO-1 at Lys229 as a negative regulator antagonized by JNK phosphorylation, and PTEN repression as a survival mechanism activating Akt.

    Evidence In vitro/in vivo SUMOylation with K229R and S63A/S73A mutants and AP-1 reporters; PTEN promoter ChIP/reporter with siRNA epistasis in null cells

    PMID:10788439 PMID:16676006

    Open questions at the time
    • SUMO E3 ligase and dynamics in vivo not defined
    • Crosstalk between SUMO and ubiquitin pathways on c-Jun not resolved
  10. 2001 Medium

    Demonstrated phospho-c-Jun confers selective protection against DNA-damaging agents.

    Evidence Stable dominant-negative S63A/S73A expression with AP-1 reporter and cytotoxicity assays

    PMID:11352915

    Open questions at the time
    • Target genes mediating DNA-damage protection not identified
    • Single-lab correlative apoptosis readout
  11. 2002 Medium

    Extended c-Jun's regulatory network to TGF-β (via Ski/Smad2 repression) and revealed Menin as a downstream uncoupler of MAPK activation from c-Jun phosphorylation.

    Evidence Co-IP of c-Jun/Ski/Smad2 ternary complex with reporter and TGF-β/JNK manipulation; in vitro kinase assays with Menin domain mapping

    PMID:12034730 PMID:12226747

    Open questions at the time
    • Direct versus indirect nature of Menin's inhibition unresolved
    • Ski complex dynamics shown in single lab
  12. 2003 High

    Established c-Jun's roles in epidermal wound healing via an HB-EGF/EGFR autocrine loop and in mutual nuclear retention with ATF2.

    Evidence Epidermis-conditional knockout with migration and EGFR assays and HB-EGF rescue; subcellular fractionation/imaging with NES/NLS mutagenesis and co-IP; ATF3 co-expression neurite assay

    PMID:12791271 PMID:12791272 PMID:14667575 PMID:16511568

    Open questions at the time
    • ATF2 nuclear-retention mechanism studied in limited contexts
    • ATF3–c-Jun physical interaction only inferred
  13. 2004 Medium

    Showed c-Jun potentiates chemotherapy-induced apoptosis by transcriptionally inducing and stabilizing p73.

    Evidence c-jun null cells with rescue, p73 half-life/pulse-chase, proteasome inhibition, and apoptosis assays

    PMID:15302867

    Open questions at the time
    • Mechanism of p73 protein stabilization by c-Jun not defined
    • Single-lab observation
  14. 2008 High

    Defined c-Jun as a negative regulator of Schwann cell myelination and identified a non-transcriptional nucleolar role in rRNA processing via DDX21.

    Evidence Conditional/transgenic Schwann cell overexpression with co-culture and nerve-transection assays; siRNA knockdown with rescue, co-IP, localization, and rRNA processing readout

    PMID:18180292 PMID:18490512

    Open questions at the time
    • Molecular basis of c-Jun's nucleolar function beyond DDX21 binding unclear
    • Cross-antagonism with Krox-20 mechanism not fully resolved
  15. 2010 High

    Established a JNK–c-Jun–Mkp1 negative feedback loop controlling neuronal apoptosis.

    Evidence ChIP and in vitro promoter binding, microinjection/overexpression, Mkp1 knockout mice, and sympathetic neuron apoptosis assays

    PMID:20702711

    Open questions at the time
    • Generality of the feedback loop beyond sympathetic neurons not tested
  16. 2012 High

    Defined c-Jun as the master regulator of the Schwann cell repair program in Wallerian degeneration, directly activating GDNF and Artemin to drive axonal regeneration.

    Evidence Schwann cell-conditional knockout, target gene ChIP, recombinant GDNF/Artemin rescue, Ret knockout epistasis, and injury/recovery models

    PMID:22753894 PMID:22920255

    Open questions at the time
    • Full transcriptional repertoire of the repair program not enumerated
    • Separation of regeneration versus survival outputs incompletely defined
  17. 2013 High

    Identified c-Jun as required for limb joint specification through direct regulation of Wnt9a and Wnt16.

    Evidence Limb-conditional knockout, enhancer reporters, promoter screen, and chromatin/functional analysis of Wnt genes

    PMID:23475960

    Open questions at the time
    • Upstream signals positioning c-Jun in the joint interzone not defined
  18. 2015 Medium

    Revealed c-Jun as a barrier to iPSC reprogramming by enforcing mesenchymal identity and suppressing pluripotency genes.

    Evidence shRNA knockdown, dominant-negative expression, reprogramming assays, and expression profiling

    PMID:26098572

    Open questions at the time
    • Direct target genes mediating the MET block not fully defined
    • Single-lab functional study
  19. 2016 Medium

    Connected c-Jun stability and activity to metabolic and redox state via O-GlcNAcylation, USP6 deubiquitination, and the PRR7/FBW7 axis.

    Evidence OGT modulation with S73A mutant, PSAT1/CBS ChIP and ferroptosis assays; DUB screen with co-IP/ubiquitination; synaptonuclear trafficking with PRR7–FBW7–c-Jun co-IP and excitotoxicity assays

    PMID:27458189 PMID:29061731 PMID:31394193

    Open questions at the time
    • Interplay among the multiple stability inputs not integrated
    • Each axis validated in a single lab/cell context
  20. 2019 Medium

    Identified KDM4B as a chromatin-associated coactivator of c-Jun on pro-migratory target promoters.

    Evidence Co-IP, ChIP on IL-8/MMP1/ITGAV promoters, KDM4B knockdown, and migration assays

    PMID:30683841

    Open questions at the time
    • Whether demethylase catalytic activity is strictly required for coactivation not fully resolved
    • Single-lab study
  21. 2022 Medium

    Established lactate as an intracellular ligand that protects c-Jun from FBW7-mediated degradation, making c-Jun a metabolic sensor in myeloid differentiation.

    Evidence LC-MS metabolite–protein interaction screen, CRISPR disruption, co-IP, and ubiquitination assays

    PMID:35263597

    Open questions at the time
    • Lactate-binding site on c-Jun not mapped
    • Single-lab/single-system observation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, sometimes opposing post-translational inputs (phosphorylation, SUMOylation, ubiquitination, O-GlcNAcylation, metabolite binding) are integrated to set c-Jun activity and stability in a given cell context remains unresolved.
  • No unified quantitative model of c-Jun regulatory inputs
  • Structural basis for metabolite (lactate) sensing unknown
  • Context-specific E3 ligase usage not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 1
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 1
Partners
ARATF2DDX21FOSGRJNKMYODRB1
Complex memberships
AP-1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 c-Jun dimerizes as a homodimer to bind the AP-1 DNA site in vitro, while c-Jun/c-Fos heterodimers bind the AP-1 element ~25-fold more efficiently than c-Jun homodimers, establishing the basis for differential DNA-binding affinity of AP-1 complexes. In vitro translation, gel retardation/EMSA, co-translation dimerization assay Cell High 3142692
1990 c-Jun and the glucocorticoid receptor (GR) reciprocally repress each other's transcriptional activation through a mechanism independent of DNA binding, requiring the leucine zipper of c-Jun and the ligand-binding/DNA-binding domains of GR; bacterially expressed c-Jun disrupts GR-GRE complexes in gel retardation assays. Transient transfection reporter assay, mutant analysis, gel retardation with bacterially expressed proteins Cell High 2169353
1991 Two serine residues in the c-Jun N-terminal transactivation domain (within the A1 domain) are phosphorylated in response to mitogens, phorbol esters, and activated Ras by MAP kinases (pp54 and pp42/44), and this phosphorylation positively regulates c-Jun transactivation activity. In vitro kinase assay, phosphorylation site mapping, reporter transcription assay Nature High 1922387
1991 c-Jun and MyoD physically interact in vivo and in vitro via the leucine zipper domain of c-Jun and the helix-loop-helix region of MyoD, resulting in mutual transcriptional repression; c-Jun inhibits MyoD-dependent myogenesis. Co-immunoprecipitation (in vivo), in vitro binding assay, transient transfection reporter assay, mutational analysis Cell High 1310896
1993 c-Jun is essential for normal mouse hepatogenesis and fetal development; c-jun-null embryos die at mid-to-late gestation with impaired hepatogenesis and altered fetal liver erythropoiesis, establishing a required in vivo role for c-Jun in liver development. Targeted gene knockout in mice (homologous recombination), chimeric mouse analysis Nature High 8371760
1994 A subfamily of MAP kinases designated stress-activated protein kinases (SAPKs/p54s, later called JNKs) are identified as the principal c-Jun N-terminal kinases; they are activated by cellular stress and TNF-α (but not mitogens) and are more active than Erk1/2 in phosphorylating the c-Jun transactivation domain, defining a new stress/TNF-α signaling pathway regulating c-Jun. Molecular cloning, in vitro kinase assay with substrate specificity profiling, cell stimulation assays Nature High 8177321
1995 The DNA-binding activity of c-Jun is regulated by the phosphorylation state of a cluster of Thr/Ser residues near its C-terminus; C-terminal dephosphorylation (activating DNA binding) is an indirect consequence of a separate N-terminal phosphorylation event, indicating intramolecular signal transduction within c-Jun. Phosphorylation site mutagenesis, DNA-binding assay, phorbol ester stimulation The EMBO journal Medium 7744008
1996 c-Jun is required for Ras-induced cellular transformation; c-jun null fibroblasts lack anchorage independence, loss of contact inhibition, and tumorigenicity in response to activated Ras, and these defects are rescued by re-expression of c-Jun, establishing c-Jun as an essential effector of Ras transformation. Genetic epistasis using c-jun null fibroblasts, ras transformation assay, soft agar/focus assay, nude mouse tumorigenicity Molecular and cellular biology High 8754851
1996 c-Jun interacts with the DNA-binding domain/hinge region of the androgen receptor (AR), supporting AR-mediated transactivation in the absence of c-Jun DNA binding or c-Fos interaction; this interaction was demonstrated using a modified yeast two-hybrid system in COS cells. Transient transfection reporter assay, modified yeast two-hybrid in mammalian cells (Cos cells) The Journal of biological chemistry Medium 8798722
1996 c-Jun is degraded via multi-ubiquitination, whereas the related family member JunD is not efficiently ubiquitinated and has a longer half-life; the N-terminal delta-domain of c-Jun contains the determinant for differential ubiquitination between c-Jun and JunD. In vivo ubiquitination assay, mutational analysis, pulse-chase protein stability assay Biological chemistry Medium 8922589
1998 JNK binds to c-Jun in vivo through multiple interaction regions: the c-Jun delta-region docking site is essential, and the C-terminal DNA-binding domain harbors an auxiliary interaction domain capable of independently binding JNK; JNK binding does not require its catalytic activity nor the phosphoacceptor sites in c-Jun, and activated JNK can phosphorylate c-Jun without necessarily dissociating from it. In vivo co-immunoprecipitation, in vitro binding with purified recombinant proteins, mutagenesis The Journal of biological chemistry High 9837920
1998 The retinoblastoma protein (Rb) binds c-Jun via the leucine zipper region of c-Jun and the B pocket plus C-terminal domain of Rb, and stimulates c-Jun transcriptional activity from an AP-1 consensus sequence; this complex forms in terminally differentiating keratinocytes and in early G1; HPV16 E7 (which binds both) inhibits Rb activation of c-Jun. Co-immunoprecipitation, transient transfection reporter assay, mutagenesis, cell-cycle synchronized cells The EMBO journal Medium 9545246
1998 In PC12 cells, ERK pathway activation leads to both increased c-Jun expression and phosphorylation (on Ser63/73); constitutively active c-Jun induces neuronal differentiation independently of upstream signals, while dominant-negative c-JunbZIP prevents MEK1-induced neurite outgrowth, establishing c-Jun as a downstream effector of ERK for neuronal differentiation. Constitutively active/dominant-negative expression, MEK1 activation, PC12 cell differentiation assay The EMBO journal Medium 9687508
1999 c-Jun promotes G1-to-S phase progression by directly controlling transcription of cyclin D1; this function is independent of Ser63/73 phosphorylation. Additionally, c-Jun protects cells from UV-induced apoptosis and cooperates with NF-κB against TNFα-induced apoptosis; anti-apoptotic function against UV requires Ser63/73 phosphorylation. c-Jun null fibroblasts, cyclin D1 reporter assay, serine-to-alanine phosphorylation mutants, apoptosis assays The EMBO journal High 9878062
1999 c-Jun negatively regulates p53 transcription by directly binding to a variant AP-1 site in the p53 promoter; loss of c-Jun leads to elevated p53 and p21 expression and impaired G1-CDK/E2F activation; deletion of p53 rescues all proliferation defects of c-jun-null cells, establishing p53 repression as the rate-limiting function of c-Jun in fibroblast proliferation. c-Jun null fibroblasts, p53 promoter-reporter assay, ChIP/AP-1 site mutagenesis, p53 knockout epistasis Genes & development High 10072388
1999 c-Jun null embryos show impaired hepatogenesis and extensive apoptosis in fetal liver; c-jun-/- fetal liver cells can reconstitute hematopoietic compartments in lethally irradiated recipients (no cell-autonomous hematopoietic defect); heart outflow tract malformations (truncus arteriosus-like) are also observed, identifying novel roles for c-Jun in hepatocyte survival and cardiac development. Targeted gene knockout, chimeric mouse reconstitution, apoptosis assays, developmental morphology The Journal of cell biology High 10352021
2000 SUMO-1 covalently modifies c-Jun predominantly at Lys-229; this modification negatively regulates c-Jun transcriptional activity (SUMO-1-deficient K229R mutant shows increased AP-1 transactivation). JNK activation reduces SUMO-1 modification of c-Jun; loss of the JNK phosphorylation sites Ser63/Ser73 greatly enhances SUMO-1 conjugation, linking JNK phosphorylation to decreased SUMO-1 modification. In vitro and in vivo SUMOylation assay, site-directed mutagenesis (K229R, S63A/S73A), AP-1 reporter assay The Journal of biological chemistry High 10788439
2000 c-Jun promotes cellular survival by negatively regulating PTEN expression: c-Jun binds a variant AP-1 site in the PTEN promoter to suppress PTEN transcription, leading to Akt pathway activation; c-jun-/- fibroblasts show elevated PTEN and are sensitive to nutrient deprivation; siRNA knockdown of PTEN rescues death from c-Jun deficiency. Inducible c-Jun expression, AP-1 reporter on PTEN promoter, ChIP, siRNA knockdown epistasis, c-jun null cells Cell death and differentiation High 16676006
2001 Stable expression of a non-phosphorylatable dominant negative c-Jun(S63A,S73A) inhibits AP-1-driven transcription and increases sensitivity to DNA-damaging agents (associated with enhanced apoptosis) but does not affect sensitivity to non-DNA-damaging cytotoxic agents, demonstrating a selective protective role for phospho-c-Jun in DNA damage responses. Stable expression of dominant-negative phosphorylation mutant, AP-1 reporter assay, cytotoxicity assays The Journal of biological chemistry Medium 11352915
2002 c-Jun directly interacts with the oncoprotein Ski and enhances Ski association with Smad2 under basal conditions, maintaining repression of Smad2-responsive genes; TGF-β signaling induces dissociation of the c-Jun/Ski complex, relieving active repression; JNK pathway activation suppresses TGF-β-induced dissociation of c-Jun from Ski. Co-immunoprecipitation, reporter assay, TGF-β stimulation, JNK pathway manipulation The Journal of biological chemistry Medium 12034730
2002 Menin inhibits JNK-mediated phosphorylation of c-Jun (and ERK-mediated phosphorylation of JunD/Elk-1) without affecting JNK1 or ERK2 activation itself, indicating that Menin acts downstream of MAPKs to uncouple kinase activation from nuclear substrate phosphorylation; distinct N-terminal Menin domains mediate inhibition of ERK vs. JNK pathways. In vitro kinase assay, overexpression of Menin, deletion mutagenesis of Menin Oncogene Medium 12226747
2003 c-Jun is required for epidermal leading edge organization and wound healing; conditional deletion of c-Jun in keratinocytes prevents EGFR activation at wound edges; c-Jun controls an EGFR autocrine loop by transcriptionally regulating HB-EGF, and conditioned medium or HB-EGF rescues migration defects. Conditional knockout (epidermis-specific), scratch migration assay, EGFR activation assay, conditioned medium rescue Developmental cell High 12791271 12791272
2003 ATF2 and c-Jun physically associate; dimerization of c-Jun with ATF2 in the nucleus prevents nuclear export of ATF2 (which contains a leucine-zipper nuclear export signal), promoting transcriptional activation of the c-jun promoter; c-Jun-dependent nuclear retention of ATF2 occurs during RA-induced differentiation and UV-induced cell death. Subcellular fractionation, live-cell imaging, FRAP-like localization assays, co-immunoprecipitation, promoter reporter assay, NES/NLS mutagenesis The EMBO journal Medium 16511568
2003 ATF3 physically associates with c-Jun and significantly enhances c-Jun-mediated neurite sprouting in neuronal-like cell lines; co-expression of both factors beyond the additive effect of either alone suggests cooperation through direct protein–protein interaction. Co-expression/transfection, neurite sprouting assay, co-immunoprecipitation (physical association inferred) Brain research. Molecular brain research Low 14667575
2004 c-Jun contributes to p73 induction by cisplatin: c-Jun transcriptionally activates p73 and increases p73 protein stability by preventing proteasome-mediated degradation, potentiating p73 transcriptional activity and apoptosis; c-jun-/- cells are resistant to cisplatin-induced apoptosis and show defective p73 induction; re-expression of c-Jun restores sensitivity. c-Jun null cells, ectopic c-Jun expression, p73 half-life/pulse-chase, proteasome inhibitor assay, apoptosis assay The Journal of biological chemistry Medium 15302867
2007 Methylation-controlled J protein (MCJ), a Golgi-localized cochaperone, is required for c-Jun degradation; loss of MCJ leads to elevated c-Jun protein levels and c-Jun-mediated transcriptional induction of the ABCB1 drug transporter, conferring drug resistance. siRNA knockdown of MCJ, c-Jun protein stability assay, AP-1 reporter, ABCB1 expression analysis Molecular and cellular biology Medium 17283040
2008 c-Jun negatively regulates the myelinating Schwann cell phenotype: at physiological levels c-Jun inhibits myelin gene activation by Krox-20/EGF, drives myelinating cells back to an immature state after nerve injury, and shows cross-antagonism with Krox-20; enforced c-Jun expression inhibits myelination in co-cultures. Conditional transgenic overexpression, co-culture myelination assay, nerve transection in vivo, reporter assays The Journal of cell biology High 18490512
2008 c-Jun depletion inhibits 28S and 18S rRNA accumulation and causes partial translocation of RNA helicase DDX21 from the nucleolus to the nucleoplasm; c-Jun directly interacts with DDX21, and exogenous c-Jun rescues DDX21 nucleolar localization and rRNA binding, revealing a non-transcriptional, nucleolar role for c-Jun in rRNA processing. siRNA knockdown, rRNA processing assay, co-immunoprecipitation (c-Jun–DDX21 interaction), subcellular fractionation/immunofluorescence, rescue by exogenous c-Jun The Journal of biological chemistry High 18180292
2010 Mkp1 (a MAPK phosphatase) is a direct c-Jun target gene in sympathetic neurons: c-Jun and ATF2 bind two conserved ATF sites in the Mkp1 promoter (demonstrated by ChIP and in vitro binding); Mkp1 overexpression inhibits JNK-mediated c-Jun phosphorylation and protects neurons from apoptosis; Mkp1 knockdown accelerates death, establishing a negative feedback loop. ChIP, in vitro promoter binding, microinjection/overexpression, Mkp1 knockout mice, sympathetic neuron apoptosis assay The Journal of neuroscience High 20702711
2012 c-Jun in Schwann cells directly regulates GDNF and Artemin (ligands for the Ret receptor) as novel target genes; after nerve injury, Schwann cell-specific c-Jun deletion impairs axonal regeneration and causes motoneuron death; administration of recombinant GDNF and Artemin substantially rescues regeneration defects, and neuron-specific Ret deletion recapitulates regeneration (but not survival) defects. Schwann cell-conditional c-Jun knockout, neurotrophic factor ChIP/target gene analysis, recombinant protein rescue, neuron-specific Ret knockout epistasis The Journal of cell biology High 22753894
2012 c-Jun activation in Schwann cells is a global regulator of Wallerian degeneration: c-Jun governs trophic factor expression, adhesion molecule expression, regeneration track formation, myelin clearance, and activates a repair/dedifferentiation program; c-Jun-deficient Schwann cells form a dysfunctional repair cell leading to failure of functional recovery and neuronal death. Schwann cell-conditional c-Jun knockout, nerve crush/transection injury models, functional recovery assays, gene expression analysis Neuron High 22920255
2013 c-Jun is required for joint specification during skeletal development: c-Jun is specifically expressed in joint interzones, conditionally deleting c-Jun from limb bud mesenchyme severely impairs initiation and differentiation of all limb joints, and c-Jun directly regulates Wnt9a and Wnt16 expression in the joint interzone. Conditional knockout (limb-specific), transgenic reporter (enhancer-driven), in silico promoter screen, chromatin/functional analysis of Wnt target genes Genes & development High 23475960
2015 c-Jun acts as a barrier to iPSC reprogramming: c-Jun activates mesenchymal-related genes and broadly suppresses pluripotency genes, blocking the obligatory mesenchymal-to-epithelial transition during reprogramming; shRNA inhibition, dominant-negative c-Jun, or Jdp2 expression enhances reprogramming and can replace Oct4 among Yamanaka factors. shRNA knockdown, dominant-negative expression, iPSC reprogramming assay, gene expression profiling Nature cell biology Medium 26098572
2016 O-GlcNAcylation of c-Jun at Ser73 stabilizes c-Jun protein, promotes its nuclear accumulation and transcriptional activity, and enables c-Jun to directly bind the PSAT1 and CBS promoters to upregulate GSH synthesis, thereby antagonizing ferroptosis; O-GlcNAc-deficient c-Jun(S73A) mutant fails to rescue GSH synthesis or inhibit ferroptosis. OGT inhibitor/activator treatment, c-Jun-WT vs S73A mutant overexpression, ChIP on PSAT1/CBS promoters, GSH measurement, ferroptosis assay Cellular signalling Medium 31394193
2016 USP6 deubiquitinase interacts with c-Jun, antagonizes its ubiquitination (dependent on USP6 enzyme activity), and thereby stabilizes c-Jun protein and upregulates AP-1 signaling; USP6 overexpression promotes cell invasion. DUB library screen, co-immunoprecipitation, ubiquitination assay, AP-1 reporter, invasion assay Molecular and cellular biology Medium 29061731
2016 PRR7, a synaptic component, accumulates in hippocampal neuron nuclei following NMDAR activity and inhibits ubiquitination of c-Jun by E3 ligase SCF(FBW7), increasing c-Jun-dependent transcriptional activity and promoting neuronal death; PRR7 knockdown attenuates NMDAR-mediated excitotoxicity in a c-Jun-dependent manner. Synaptonuclear trafficking assay, co-immunoprecipitation (PRR7–FBW7–c-Jun), ubiquitination assay, c-Jun reporter, siRNA knockdown, excitotoxicity assay The EMBO journal Medium 27458189
2019 KDM4B histone demethylase physically interacts with c-Jun on the promoters of IL-8, MMP1, and ITGAV via its demethylation activity, acting as a coactivator of c-Jun; depletion of KDM4B decreases integrin αV expression and cell migration. Co-immunoprecipitation, ChIP on target promoters, KDM4B knockdown, migration assay Cell death & disease Medium 30683841
2022 Lactate interacts with c-Jun protein to protect it from FBW7 ubiquitin-ligase-mediated degradation in myeloid cells; this was identified by LC-MS followed by CRISPR-Cas9-mediated gene disruption, positioning lactate as an intracellular sensor ligand for c-Jun stability and c-Jun as a sensor of intracellular lactate in MDSC differentiation. LC-MS metabolite–protein interaction screen, CRISPR-Cas9 gene disruption, co-immunoprecipitation, ubiquitination assay Cell reports Medium 35263597

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 The stress-activated protein kinase subfamily of c-Jun kinases. Nature 2462 8177321
1991 Phosphorylation of c-jun mediated by MAP kinases. Nature 1430 1922387
1990 Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell 1220 2169353
1988 c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities. Cell 1046 3142692
2019 c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 727 31802004
2012 c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 680 22920255
1999 c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. The EMBO journal 562 9878062
1999 Control of cell cycle progression by c-Jun is p53 dependent. Genes & development 490 10072388
1993 c-jun is essential for normal mouse development and hepatogenesis. Nature 475 8371760
1999 Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 456 10557107
1992 Functional antagonism between c-Jun and MyoD proteins: a direct physical association. Cell 415 1310896
2000 c-Jun and p53 activity is modulated by SUMO-1 modification. The Journal of biological chemistry 344 10788439
2008 c-Jun is a negative regulator of myelination. The Journal of cell biology 330 18490512
1998 Differential regulation of c-Jun by ERK and JNK during PC12 cell differentiation. The EMBO journal 291 9687508
1996 Cellular transformation and malignancy induced by ras require c-jun. Molecular and cellular biology 250 8754851
2011 c-Jun, at the crossroad of the signaling network. Protein & cell 241 22180088
2003 c-Jun regulates eyelid closure and skin tumor development through EGFR signaling. Developmental cell 233 12791272
1999 Functions of c-Jun in liver and heart development. The Journal of cell biology 223 10352021
2012 c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling. The Journal of cell biology 221 22753894
2000 c-Jun and the transcriptional control of neuronal apoptosis. Biochemical pharmacology 221 11007936
2004 Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death. The Journal of cell biology 192 14757751
1998 Stress signals for apoptosis: ceramide and c-Jun kinase. Oncogene 191 9916990
1989 Tissue-specific expression of c-jun and junB during organogenesis in the mouse. Development (Cambridge, England) 191 2480878
2003 c-Jun is essential for organization of the epidermal leading edge. Developmental cell 189 12791271
1999 Signal transduction by the c-Jun N-terminal kinase. Biochemical Society symposium 185 10207617
1991 Overexpression of c-jun, junB, or junD affects cell growth differently. Proceedings of the National Academy of Sciences of the United States of America 156 1924349
2006 c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer. Human pathology 155 16733206
2006 c-Jun promotes cellular survival by suppression of PTEN. Cell death and differentiation 135 16676006
2015 The oncogene c-Jun impedes somatic cell reprogramming. Nature cell biology 118 26098572
1995 Intramolecular signal transduction in c-Jun. The EMBO journal 116 7744008
2019 Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance. Gut 111 31118247
2015 The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma. Science signaling 111 26286024
2001 Protective role for c-Jun in the cellular response to DNA damage. The Journal of biological chemistry 102 11352915
1994 Regulation of c-jun expression during hypoxic and low-glucose stress. Molecular and cellular biology 101 8035787
2006 Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. The EMBO journal 96 16511568
2008 c-Jun expression, activation and function in neural cell death, inflammation and repair. Journal of neurochemistry 93 18793328
1998 Rb binds c-Jun and activates transcription. The EMBO journal 90 9545246
1996 c-Jun can mediate androgen receptor-induced transactivation. The Journal of biological chemistry 90 8798722
2022 Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis. Cell reports 85 35263597
2003 ATF3 enhances c-Jun-mediated neurite sprouting. Brain research. Molecular brain research 85 14667575
2019 O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer. Cellular signalling 83 31394193
2002 Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation. Oncogene 82 12226747
2016 miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis. Nature communications 78 27173017
2014 Increased expression of c-Jun in nonalcoholic fatty liver disease. Laboratory investigation; a journal of technical methods and pathology 77 24492282
2000 Extracellular glucose influences osteoblast differentiation and c-Jun expression. Journal of cellular biochemistry 77 10967557
2004 RANKing c-Jun in osteoclast development. The Journal of clinical investigation 72 15314680
2014 Elevated DDX21 regulates c-Jun activity and rRNA processing in human breast cancers. Breast cancer research : BCR 70 25260534
2004 c-Jun regulates the stability and activity of the p53 homologue, p73. The Journal of biological chemistry 67 15302867
2003 C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis. Neuroscience 66 12770554
2000 c-Jun promotes neurite outgrowth and survival in PC12 cells. Brain research. Molecular brain research 62 11072092
1989 Expression of c-jun protooncogene in human myelomonocytic cells. Blood 62 2477086
2010 Mkp1 is a c-Jun target gene that antagonizes JNK-dependent apoptosis in sympathetic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 20702711
2005 Differential regulation of c-jun and CREB by acrolein and 4-hydroxynonenal. Free radical biology & medicine 57 16337876
2008 c-Jun supports ribosomal RNA processing and nucleolar localization of RNA helicase DDX21. The Journal of biological chemistry 56 18180292
1991 Expression of c-jun during macrophage differentiation of HL-60 cells. Blood 53 1904283
2012 c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases. The open rheumatology journal 52 23028407
2008 c-Jun N-terminal kinase pathways in diabetes. The international journal of biochemistry & cell biology 51 18678273
2011 c-Jun expression in human neuropathies: a pilot study. Journal of the peripheral nervous system : JPNS 50 22176144
2007 Methylation-controlled J protein promotes c-Jun degradation to prevent ABCB1 transporter expression. Molecular and cellular biology 48 17283040
2011 Crosstalk between c-Jun and TAp73alpha/beta contributes to the apoptosis-survival balance. Nucleic acids research 47 21459846
2013 c-Jun-mediated anticancer mechanisms of tylophorine. Carcinogenesis 46 23385061
2011 c-Jun N-terminal kinases in memory and synaptic plasticity. Reviews in the neurosciences 46 21605011
2021 Upregulation of LAMB1 via ERK/c-Jun Axis Promotes Gastric Cancer Growth and Motility. International journal of molecular sciences 45 33435161
2017 Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines. PloS one 45 28323861
1997 Complex mechanisms for c-fos and c-jun degradation. Molecular biology reports 45 9228281
2016 Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer. Stem cells (Dayton, Ohio) 44 27341307
2017 TGF-β1 induces Fstl1 via the Smad3-c-Jun pathway in lung fibroblasts. American journal of physiology. Lung cellular and molecular physiology 42 28495857
2014 Niclosamide enhances ROS-mediated cell death through c-Jun activation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 39 24750999
2013 c-Jun N-terminal kinase - c-Jun pathway transactivates Bim to promote osteoarthritis. Canadian journal of physiology and pharmacology 39 24502636
1998 Analysis of the interaction between c-Jun and c-Jun N-terminal kinase in vivo. The Journal of biological chemistry 39 9837920
2002 c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity. The Journal of biological chemistry 38 12034730
1993 Estrogen induces expression of c-jun and jun-B protooncogenes in specific rat uterine cells. Endocrinology 38 8319568
2013 c-Jun is required for the specification of joint cell fates. Genes & development 37 23475960
2021 BUB1B promotes extrahepatic cholangiocarcinoma progression via JNK/c-Jun pathways. Cell death & disease 36 33431813
1996 Differential regulation of c-Jun and JunD by ubiquitin-dependent protein degradation. Biological chemistry 36 8922589
2019 C-Jun drives melanoma progression in PTEN wild type melanoma cells. Cell death & disease 35 31378787
2012 Transcriptional regulation of PES1 expression by c-Jun in colon cancer. PloS one 35 22860098
2019 KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis. Cell death & disease 34 30683841
2019 Curcumin Inhibits ERK/c-Jun Expressions and Phosphorylation against Endometrial Carcinoma. BioMed research international 34 32083122
2016 Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. The EMBO journal 34 27458189
2010 BEX2 has a functional interplay with c-Jun/JNK and p65/RelA in breast cancer. Molecular cancer 33 20482821
2021 Higenamine alleviates allergic rhinitis by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. Phytomedicine : international journal of phytotherapy and phytopharmacology 32 33945919
2007 c-Jun expression and activation are restricted to CD30+ lymphoproliferative disorders. The American journal of surgical pathology 32 17325487
2002 JNK3 contributes to c-jun induction and apoptosis in 4-hydroxynonenal-treated sympathetic neurons. Journal of neuroscience research 32 12424734
2001 Regulation of connexin43 expression by c-fos and c-jun in myometrial cells. Cell communication & adhesion 32 12064606
1996 c-Jun stimulates origin-dependent DNA unwinding by polyomavirus large Tantigen. The EMBO journal 32 8896457
2017 MALT1 promotes melanoma progression through JNK/c-Jun signaling. Oncogenesis 31 28759024
2018 miR-139-5p inhibits isoproterenol-induced cardiac hypertrophy by targetting c-Jun. Bioscience reports 30 29440459
2017 Ubiquitin-Specific Protease USP6 Regulates the Stability of the c-Jun Protein. Molecular and cellular biology 30 29061731
2004 FOXO1 and c-jun transcription factors mRNA are modulated in endometriosis. Molecular human reproduction 30 15501904
1994 Phosphorylation of the c-Fos and c-Jun HOB1 motif stimulates its activation capacity. Nucleic acids research 30 7816602
2015 c-Jun regulates adipocyte differentiation via the KLF15-mediated mode. Biochemical and biophysical research communications 28 26692489
2020 KDM5c Promotes Colon Cancer Cell Proliferation Through the FBXW7-c-Jun Regulatory Axis. Frontiers in oncology 27 33042830
1999 c-jun Is dispensable for developmental cell death and axogenesis in the retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 10341238
2016 MAGE-A1 promotes melanoma proliferation and migration through C-JUN activation. Biochemical and biophysical research communications 26 27045082
2013 BAG3 is upregulated by c-Jun and stabilizes JunD. Biochimica et biophysica acta 26 24140207
2022 Transcription factor c-Jun modulates GLUT1 in glycolysis and breast cancer metastasis. BMC cancer 25 36476606
2006 Vaccinia virus B1R kinase interacts with JIP1 and modulates c-Jun-dependent signaling. Journal of virology 25 16840345
1996 C-fos and c-jun expression in human endometrium and myometrium. Molecular and cellular endocrinology 25 8737385
2022 NAP1L1 promotes tumor proliferation through HDGF/C-JUN signaling in ovarian cancer. BMC cancer 24 35351053

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