Affinage

FOSL1

Fos-related antigen 1 · UniProt P15407

Length
271 aa
Mass
29.4 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOSL1 (FRA-1) is a serum-inducible immediate-early FOS-family bZIP transcription factor that, despite lacking classical transactivation domains, functions as an AP-1 component to drive tumor invasion, epithelial-to-mesenchymal transition, and metastasis (PMID:3133553, PMID:9819396, PMID:25301070). Its accumulation in oncogenically transformed cells is established by a dual mechanism: transcriptional autoregulation through an AP-1 site in its own first intron, and RAS-MEK/ERK-dependent posttranslational stabilization that markedly extends protein half-life (PMID:7791782, PMID:12773579); this stabilization depends on an intact ERK phosphorylation site, and analogous MEK5-ERK5 phosphorylation and integrin αVβ3/uPAR–FAK-SRC-ERK2 signaling converge to control FRA-1 activity and turnover (PMID:11756554, PMID:12622723, PMID:29382358). FRA-1 transactivation requires heterodimerization with JUN-family partners, and FRA-1/c-Jun heterodimerization reciprocally stabilizes c-Jun in an ERK-dependent manner (PMID:12773579, PMID:20543861). As a sequence-specific factor it directly binds promoters and intragenic/enhancer elements to activate a pro-invasive and pro-metastatic program, including the EMT regulators ZEB1, ZEB2, and TGFβ1, the matrix protease genes MMP-1, MMP-9, and PLAU/uPA, the oncogene HMGA1, integrin ITGB4, and the glycolytic genes SLC2A1, ENO1, and LDHA, while repressing differentiation genes such as C/EBPα and the macrophage gene Arg1 (PMID:21486951, PMID:25301070, PMID:25200076, PMID:30990796, PMID:31300541, PMID:39748430). FRA-1 frequently exploits pre-existing chromatin loops to recruit RNA Polymerase II and assembles Mediator-associated super-enhancers at stemness and pro-metastatic loci (PMID:31300541, PMID:33794365). Genetically, FRA-1 can substitute for c-Fos in vivo, rescuing osteopetrosis in c-fos-mutant mice, and acts as a limiting factor for osteoclast differentiation (PMID:10199556, PMID:10655067). Beyond cancer it has tissue-protective and immunoregulatory roles: it preserves Klotho during acute kidney injury, drives cardiomyocyte proliferation during heart regeneration via JunB, and acts as a negative regulator of type I interferon signaling by translocating to the cytoplasm to block TRAF3/TRIF/TBK1 assembly (PMID:28049150, PMID:34188056, PMID:36565807).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1988 High

    Established FRA-1 as a distinct FOS-family immediate-early gene, answering whether the Fos-related antigen was an independent serum-responsive regulator rather than a c-Fos artifact.

    Evidence cDNA cloning, sequencing, and Northern analysis of serum-stimulated rat fibroblasts

    PMID:3133553

    Open questions at the time
    • Did not define DNA-binding specificity or dimer partners
    • No functional role assigned
  2. 1995 High

    Showed FRA-1 is oncogenic and autoregulated despite lacking a classical transactivation domain, reframing how a transactivation-deficient factor could transform cells.

    Evidence Intron mutagenesis, Gal4-fusion transactivation assays, soft-agar and nude-mouse tumorigenesis

    PMID:7791782

    Open questions at the time
    • Mechanism of transactivation-independent transformation not resolved
    • Required dimer partner unidentified
  3. 1998 High

    Demonstrated a direct causal role for FRA-1 in epithelial-to-mesenchymal-like conversion and invasion, linking it to late-stage tumor progression.

    Evidence Retroviral FRA-1 expression in CSML0 carcinoma cells with invasion, morphology, and EMSA readouts

    PMID:9819396

    Open questions at the time
    • Direct target genes of the EMT program not yet identified
  4. 2000 High

    Genetic rescue experiments established FRA-1 as a functional in vivo substitute for c-Fos and a RANKL/c-Fos-driven effector in osteoclast differentiation.

    Evidence Retroviral rescue and transgenic rescue of c-fos-null osteopetrosis, in vitro osteoclast assays (also [#3])

    PMID:10199556 PMID:10655067

    Open questions at the time
    • Target genes downstream of FRA-1 in osteoclasts not defined
  5. 2003 High

    Resolved how FRA-1 accumulates in transformed cells, establishing combined intronic autoregulation and MEK/ERK-dependent protein stabilization as the basis for RAS-driven accumulation.

    Evidence ChIP, MEK inhibition, protein half-life and reporter assays in ras-transformed cells; ERK-site mutagenesis (also [#5, #7])

    PMID:11756554 PMID:12622723 PMID:12773579

    Open questions at the time
    • Identity of the obligate heterodimer partner in transformed cells not pinned down here
    • ERK5 versus ERK1/2 site contributions only partially separated
  6. 2010 High

    Defined a reciprocal regulatory mechanism by which FRA-1/c-Jun heterodimerization stabilizes c-Jun, coupling FRA-1 stability and dimerization to AP-1 output.

    Evidence Co-IP, protein half-life, ERK inhibition, and dimerization-deficient FRA-1 mutants in transformed thyroid cells

    PMID:20543861

    Open questions at the time
    • Degradation machinery for c-Jun in this context not fully defined
    • Ubiquitin-independent versus -dependent turnover of FRA-1 itself only partly characterized ([#11])
  7. 2014 High

    Identified the direct transcriptional targets through which FRA-1 enforces EMT, placing ZEB1/ZEB2 epistatically downstream of FRA-1.

    Evidence ChIP at tgfb1/zeb1/zeb2 loci, reporter assays, siRNA epistasis, and in vivo transplantation (with PLAU enhancer mapping in [#21])

    PMID:25200076 PMID:25301070

    Open questions at the time
    • Selectivity of FRA-1 among AP-1 dimers at these loci not fully resolved
  8. 2017 High

    Revealed a non-transcriptional, cytoplasmic function for FOSL1 as a negative regulator of type I interferon signaling, expanding its role beyond nuclear AP-1.

    Evidence Co-IP of TRAF3/TRIF/TBK1, ubiquitination assays, fractionation, and FOSL1-KO chimeric mice challenged with poly(I:C)/virus/malaria

    PMID:28049150

    Open questions at the time
    • Signal triggering nuclear-to-cytoplasmic translocation not defined
    • Structural basis of TRAF3/TRIF interference unknown
  9. 2019 High

    Showed FRA-1 acts on chromatin via pre-existing loops and ChIP-seq-scale target programs, including transcriptional repression of Arg1 in macrophages.

    Evidence ChIP-seq, 3C, transcriptional run-on, conditional macrophage Fra-1 KO with arginase rescue (also HMGA1 enhancer looping in [#27])

    PMID:30990796 PMID:31300541

    Open questions at the time
    • Determinants of activator versus repressor behavior at different loci unresolved
  10. 2021 Medium

    Connected FOSL1 to super-enhancer assembly and tissue-protective/regenerative roles, broadening its mechanism to Mediator co-association and condensate formation.

    Evidence ChIP-seq super-enhancer mapping with Mediator co-association in HNSCC, JunB Co-IP/ChIP in heart regeneration, and SMAD4-repression metastasis screen (also [#37, #33])

    PMID:33794365 PMID:34188056 PMID:34320363

    Open questions at the time
    • Mediator-selectivity mechanism not biochemically dissected
    • Single-lab models for each tissue context
  11. 2022 Medium

    Extended the FOSL1 target program to metabolic reprogramming and post-translational/upstream control, including STAT3-driven induction and DNA-binding-domain acetylation.

    Evidence ChIP and reporter assays for glycolytic genes (SLC2A1/ENO1/LDHA) with 2-DG rescue, plus STAT3/TRPM7 and Lys-116 deacetylation studies (also [#33, #38])

    PMID:36565807 PMID:37642779 PMID:39748430

    Open questions at the time
    • Enzymes controlling Lys-116 acetylation not identified
    • Many target programs validated in single cell systems

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FOSL1 selects among AP-1 dimer partners and target loci to switch between activator, repressor, super-enhancer-organizing, and cytoplasmic IFN-suppressing roles remains unresolved.
  • No unified model linking phosphorylation/acetylation state to partner choice and locus selection
  • Signal governing nuclear-cytoplasmic partitioning undefined
  • Structural basis of transactivation-domain-independent activity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
JUNJUNBMED (MEDIATOR)PARP1STAT3TRAF3
Complex memberships
AP-1Mediator-associated super-enhancer

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 FRA-1 (fra-1) was identified as a serum-inducible immediate-early gene encoding a protein with extensive amino acid homology to c-Fos, including the region showing similarity to the yeast GCN4 regulatory protein and the Jun oncogene product. Unlike c-fos, fra-1 induction by serum was delayed, but it was induced rapidly in the presence of protein synthesis inhibitors, establishing it as an immediate-early gene. cDNA library screening with anti-Fos antibodies, nucleotide sequencing, Northern blot analysis of serum-stimulated rat fibroblasts Molecular and cellular biology High 3133553
1995 Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron, which contain a consensus AP-1 site and two AP-1-like elements. Fra-1 protein fused to the Gal4 DNA-binding domain lacks transactivation function, yet overexpression of Fra-1 in rat fibroblasts confers anchorage-independent growth in vitro and tumor development in athymic mice, demonstrating oncogenic potential independent of classical transactivation. In vitro mutagenesis, stable transfection reporter assays, FosER induction system, soft-agar colony formation, nude mouse tumor assay Molecular and cellular biology High 7791782
1998 Exogenous expression of Fra-1 in epithelioid CSML0 carcinoma cells induces morphological fibroblastoid conversion, increases motility and in vitro invasiveness, and transcriptionally activates genes associated with late-stage tumor progression, establishing a direct causal role for Fra-1 in epithelial-to-mesenchymal-like transition. Retroviral transduction of Fra-1 into CSML0 cells, invasion assay, morphological analysis, AP-1 EMSA, gene expression analysis Molecular and cellular biology High 9819396
1999 Fra-1 (but not c-Fos) expressed by retroviral transduction in osteoclast-macrophage precursor cell lines causes a 10–100-fold increase in the number of precursors developing calcitonin receptors and increased bone resorption, suggesting Fra-1 is a limiting factor for full osteoclast differentiation distinct from c-Fos. Retroviral gene transfer into osteoclast precursor cell lines, calcitonin receptor assay, bone resorption assay Journal of cellular physiology Medium 10199556
2000 Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation: RANKL induces Fosl1 transcription in a c-Fos-dependent manner. All four Fos proteins (including Fra-1, which lacks transactivation domains) rescue the osteoclast differentiation block in c-fos-null mice when introduced by retroviral gene transfer; a Fra-1 transgene rescues osteopetrosis in c-fos-mutant mice in vivo. Retroviral gene transfer, transgenic mouse rescue, in vitro osteoclast differentiation assay, structure-function analysis Nature genetics High 10655067
2002 Fra-1 activates AP-1-dependent transcription in an ERK-dependent manner: a putative ERK phosphorylation site on Fra-1 must be intact for its transactivation activity. Fra-1 was identified as the distinguishing AP-1 component in mitogen-activated (transformation-sensitive) JB6 cells. Introduction of a Fra-1 expression construct into an AP-1-nonresponsive variant that underexpresses Fra-1 restored AP-1 response. Site-directed mutagenesis of Fra-1 transactivation domain, gel shift/EMSA analysis, AP-1 reporter assays, ERK-deficient cell lines Molecular and cellular biology High 11756554
2002 Fra-1 substitutes for c-Fos in AP-1-mediated signal transduction in retinal light-induced apoptosis. In knock-in mice expressing Fra-1 in place of c-Fos (Fos(Fosl1/Fosl1)), morphological features of apoptosis and AP-1 activity were indistinguishable from wild-type, demonstrating that Fra-1 can mediate both pro- and anti-apoptotic signaling without classic transactivation domains. Knock-in mouse model, light-damage apoptosis assay, AP-1 EMSA/supershift, histology Journal of neurochemistry High 11953459
2003 MEK5-ERK5 pathway activation causes phosphorylation and stabilization of Fra-1, and the C-terminal half of ERK5 is required for maximal activation of Fra-1 transactivation activity. The MEK5-ERK5 pathway-dependent phosphorylation sites on Fra-1 are distinct from those of the ERK1/2 pathway. Constitutively active MEK5 expression, kinase inhibitor experiments, transactivation reporter assays, phosphorylation analysis Genes to cells Medium 12622723
2003 Ras oncogene-dependent accumulation of Fra-1 requires both transcriptional autoregulation (via an AP-1 site in the fra-1 first intron occupied by Fra-1-containing complexes) and MEK/ERK-dependent posttranslational stabilization that dramatically increases Fra-1 protein half-life. Fra-1 transactivating activity in ras-transformed cells requires heterodimerization with a partner protein. Retroviral transformation of thyroid cells, chromatin immunoprecipitation, MEK inhibitor treatment, protein half-life analysis, transcriptional reporter assays Molecular and cellular biology High 12773579
2003 Fra-1 targets the AP-1 site adjacent to the 2G SNP in the MMP-1 promoter and is necessary for MMP-1 transcription in A2058 melanoma cells. Inhibition of Fra-1 expression preferentially downregulates transcription from the 2G SNP-containing MMP-1 promoter compared to the 1G SNP version. Fra-1 siRNA/antisense inhibition, MMP-1 promoter reporter assays with 1G vs 2G SNP constructs European journal of biochemistry Medium 14519134
2007 Fra-1 and Stat3 synergistically activate the MMP-9 gene promoter. DNA affinity precipitation and co-immunoprecipitation identified Stat3/Fra-1 and Stat3/c-Jun complexes in vivo, with c-Jun recruited to the Stat3-Fra-1 complex. A juxtaposed Stat3/AP-1 element in the MMP-9 promoter functions as an enhancersome. Neither Fra-1 alone nor Stat3 alone was sufficient for MMP-9 promoter activation. Luciferase reporter assays, DNA affinity precipitation assay, co-immunoprecipitation, promoter mutagenesis Molecular immunology Medium 17572495
2007 Ubiquitin-independent proteasomal degradation is a major pathway for Fra-1 turnover. Fra-1 shares a conserved destabilizing domain with c-Fos. Under particular conditions a fraction of cytoplasmic c-Fos is ubiquitylated leading to faster turnover, indicating multiple degradation pathways can target Fra-1 depending on activation state, protein partnership, and subcellular localization. Protein stability assays, proteasome inhibitor treatment, mutagenesis of destabilizing domains, subcellular fractionation Biochimie Medium 17825471
2009 Fra-1 binds to the MGP promoter in response to inorganic phosphate in osteoblasts, as demonstrated by in vitro DNA binding and chromatin immunoprecipitation assays. Pi-dependent induction of MGP is mediated through the ERK1/2-Fra-1 pathway: MEK1/2 inhibition abolishes Pi-stimulated Fra-1 and MGP expression, and primary osteoblasts from Fra-1-deficient mice fail to show Pi-dependent MGP upregulation. Chromatin immunoprecipitation, in vitro DNA binding assay, MEK inhibitor (U0126), Fra-1-deficient mouse primary osteoblasts, siRNA knockdown Journal of bone and mineral research High 19419315
2010 Fra-1 binds to the interleukin-6 (IL-6) promoter in macrophages to increase IL-6 production. IL-6 then acts in an autocrine fashion to skew macrophage differentiation into M2d macrophages. Fra-1 overexpression is induced in macrophages by tumor cell co-culture. ChIP assay, co-culture experiments, IL-6 promoter binding analysis, macrophage differentiation assay Cell research Medium 20386569
2010 Heterodimerization of Fra-1 with c-Jun stabilizes c-Jun in RAS-transformed cells. ERK pathway activity and Fra-1/c-Jun heterodimerization cooperate to prevent c-Jun proteasomal breakdown; phosphorylation of the Fra-1 C-terminal domain (which controls Fra-1 stability in response to ERK signaling) is required for this stabilizing effect on c-Jun. Co-immunoprecipitation, protein half-life analysis, ERK inhibitor treatment, constitutively transformed thyroid cell lines, dimerization-deficient Fra-1 mutants Oncogene High 20543861
2011 FOSL1 is a downstream effector of the PI3K/AKT signaling pathway in trophoblast cells. Nuclear FOSL1 increases during trophoblast differentiation in a PI3K/AKT-dependent manner. FOSL1 occupies the Mmp9 promoter in trophoblast cells (ChIP) and regulates Mmp9 expression; knockdown of FOSL1 abrogates trophoblast invasion in vitro and in vivo (lentiviral shRNA). PI3K/AKT inhibitors, AKT isoform-specific siRNA, ChIP, lentiviral shRNA in vivo, trophoblast invasion assay Molecular and cellular biology High 21947281
2011 Fra-1 directly suppresses the adipogenic transcription factor C/EBPα (Cebpa) by binding to the Cebpa promoter, thereby autonomously blocking adipocyte differentiation. Fra-1 transgenic mice develop severe lipodystrophy with reduced adipogenic markers; Fra-1 overexpression in adipogenic cell lines blocks their differentiation. Fra-1 transgenic mice, primary transgenic osteoblast adipogenic differentiation assay, promoter binding/ChIP assay, adipogenic cell line overexpression Journal of cell science High 21486951
2012 Fra-1 preferentially associates with c-Jun and binds to the promoter regions of the cyclin-dependent kinase inhibitor genes p21 (Cdkn1a) and p16 (Cdkn2a), leading to their transcriptional upregulation and induction of vascular senescence phenotypes in response to angiotensin II. Co-immunoprecipitation (Fra-1/c-Jun interaction), chromatin immunoprecipitation (p21 and p16 promoters), Fra-1 siRNA knockdown, senescence-associated β-galactosidase assay, in vivo Ang II infusion model FASEB journal Medium 30892941
2012 Fra-1 directly regulates MMP-9 expression in rhinovirus-infected bronchial epithelial cells. AP-1 sites in the MMP-9 promoter are required for HRV-induced MMP-9 promoter drive; EMSA/supershift identified Fra-1 in AP-1 complexes bound to the MMP-9 promoter; siRNA knockdown of Fra-1 abolished MMP-9 expression. MEK1/2 inhibition reduced Fra-1 expression and MMP-9. Formoterol and dexamethasone suppress Fra-1 and MMP-9 via reduced ERK phosphorylation. Site-directed mutagenesis of AP-1 sites, EMSA with supershift, siRNA knockdown, MEK inhibitors, pharmacological treatment Journal of immunology Medium 22461694
2012 Estrogen receptor α (ESR1) directly recruits to an estrogen response element in the Fra-1 promoter (demonstrated by ChIP), regulating Fra-1 expression in uterine stromal cells. Fra-1 in turn controls MMP9 and MMP13 expression critical for stromal extracellular matrix remodeling during decidualization. Fra-1 knockdown during in vitro decidualization blocks stromal differentiation and cell migration. ChIP (ESR1 binding to Fra-1 promoter), siRNA-mediated ESR1 silencing, Fra-1 knockdown, in vitro decidualization assay, migration assay The Journal of biological chemistry Medium 22514284
2014 Fra-1 induces EMT in mammary epithelial cells by directly binding to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1, increasing expression of TGFβ1, Zeb1, Zeb2, and Slug. Silencing of zeb1 or zeb2 (but not TGFβ inhibition alone) fully restored epithelial phenotype and decreased invasion, placing Zeb1/Zeb2 downstream of Fra-1 in EMT. ChIP (Fra-1 binding to tgfb1, zeb1, zeb2 loci), luciferase reporter assays, siRNA knockdown, ectopic Fra-1 expression in EpH4 cells, in vivo transplantation Cell death and differentiation High 25301070
2014 Fra-1 controls transcription of the uPA/Plau gene in metastatic breast cancer cells via binding to two AP-1 enhancers (ABR-1.9 and ABR-4.1, located ~1.9 and ~4.1 kb upstream of the TSS), promoting RNA Pol II recruitment and productive transcription of Plau-001 mRNA; Fra-1 also tempers expression of a minor Plau-004 transcript from ABR-1.9. ChIP, pharmacological inhibition, RNAi, RNA Pol II ChIP, chromosome conformation capture (3C) Nucleic acids research High 25200076
2017 FOSL1 is a negative regulator of type I interferon (IFN-I) signaling. Upon stimulation with poly(I:C), malaria-infected RBCs, or VSV, FOSL1 translocates from the nucleus to the cytoplasm where it inhibits interactions between TRAF3, TRIF, and TBK1 by impairing K63-linked polyubiquitination of TRAF3 and TRIF. FOSL1 knockout chimeric mice show lower parasitemia/viral titers and decreased mortality. Co-immunoprecipitation (TRAF3/TRIF/TBK1 interactions), ubiquitination assays, FOSL1 knockout chimeric mice, cellular fractionation/localization, poly(I:C) and viral stimulation mBio High 28049150
2017 FOSL1 is the main immediate-early AP-1 member induced by melanoma oncogenes and acts oncogenically by transcriptionally activating HMGA1. FOSL1 transforms melanocytes, downregulates MITF in a HMGA1-dependent manner, upregulates AXL, and re-enforces MYC, E2F3, and AP-1, enabling subcutaneous tumor growth in vivo. HMGA1 mediates FOSL1-driven migration, proliferation, and anoikis-independent growth. siRNA knockdown, ectopic expression, in vivo melanocyte transformation assay, gene expression profiling, promoter analysis Oncogene Medium 28481878
2017 MLK3 kinase drives invasion in TNBC cells through FRA-1: MLK3 expression robustly upregulates FRA-1 in breast cancer cells, accompanied by elevation of MMP-1 and MMP-9; FRA-1 silencing abrogates MLK3-induced invasion. MLK3 depletion (siRNA or CRISPR) significantly reduces FRA-1 and MMP-1/MMP-9 levels and decreases transendothelial migration. Inducible MLK3 expression, FRA-1 siRNA, CRISPR/Cas9n MLK3 deletion, invasion assay, transendothelial migration assay, MMP expression Oncogenesis Medium 28604765
2018 Integrin αVβ3/uPAR signaling leads to FAK-SRC-ERK2-mediated phosphorylation and stabilization of FRA-1, enhancing breast cancer invasion on vitronectin. Transient knockdown of uPAR reduces FRA-1 phosphorylation and stabilization; both uPAR and FRA-1 are required for vitronectin-induced invasion. Pharmacological inhibitors (FAK, SRC, ERK), uPAR siRNA knockdown, FRA-1 phosphorylation immunoblot, invasion assay on vitronectin Breast cancer research Medium 29382358
2019 Fra-1 directly binds to the arginase-1 (Arg1) promoter in macrophages (demonstrated by ChIP-seq and standard ChIP) and transcriptionally represses Arg1 expression. Macrophage-specific Fra-1-deficient mice show enhanced Arg1 expression/activity and reduced arthritis severity; the phenotype is reversed by arginase inhibition, placing Fra-1 upstream of Arg1 in macrophage inflammatory regulation. ChIP-seq, standard ChIP, luciferase reporter assay, macrophage-specific conditional Fra-1 KO mice, arginase inhibitor treatment, arthritis model The Journal of clinical investigation High 30990796
2019 Fra-1 directly regulates HMGA1 gene transcription in TNBC cells by binding to enhancer elements in the last two introns of HMGA1. Fra-1 binding is required for RNA Polymerase II recruitment at the HMGA1 promoter through pre-existing chromatin loops linking intragenic enhancers to the promoter; Fra-1 is not required for chromatin loop formation but exploits pre-existing interactions. ChIP, RNAi, transcriptional run-on assay, chromosome conformation capture (3C), mRNA analysis Molecular cancer research High 31300541
2019 PARP1 interacts with and downregulates Fra-1, reducing AP-1 transcriptional activity. Olaparib treatment or PARP1 silencing increases Fra-1 levels and AP-1 transcriptional activity. A large fraction of PARP1-regulated genes was dependent on Fra-1, as established by large-scale chromatin-bound Fra-1 proteomics screen identifying PARP1 among 118 Fra-1-interacting proteins. Co-immunoprecipitation (endogenous Fra-1-PARP1), AP-1 reporter assays, PARP1 inhibitor (olaparib), PARP1 siRNA, proteomic screen of chromatin-bound Fra-1 Cancer letters Medium 33652085
2021 FOSL1 promotes HNSCC metastasis predominantly through selective association with Mediator complex components to establish super-enhancers (SEs) at cancer stemness and pro-metastatic genes including SNAI2 and FOSL1 itself. Depletion of FOSL1 disrupts SEs and inhibits expression of these oncogenes. ChIP-seq for SE analysis, Mediator co-association assay, FOSL1 knockdown, patient-derived xenograft model, spontaneous mouse model Molecular therapy Medium 33794365
2021 FOSL1 promotes proneural-to-mesenchymal transition (PMT) in glioblastoma stem cells via UBC9-dependent CYLD SUMOylation. FOSL1 facilitates UBC9-mediated SUMOylation of CYLD, inducing K63-linked polyubiquitination of NF-κB intermediaries and NF-κB activation, which drives PMT. siRNA knockdown, ectopic expression, SUMOylation assay, ubiquitination assay, NF-κB reporter, in vivo tumor-initiating assay Molecular therapy Medium 35351656
2021 Fosl1 interacts with JunB and promotes expression of Cyclin-T1 (Ccnt1) during heart regeneration, driving cardiomyocyte proliferation. Demonstrated by Co-immunoprecipitation (Fosl1/JunB interaction), luciferase reporter assays, and ChIP analysis. Cardiomyocyte-specific dominant-negative Fosl1 impairs cardiomyocyte proliferation in X. tropicalis; Fosl1 knockdown suppresses neonatal mouse heart regeneration while overexpression improves cardiac function after myocardial infarction. Co-immunoprecipitation, luciferase reporter assay, ChIP, cardiomyocyte-specific dominant-negative transgene, siRNA knockdown, in vivo heart injury models NPJ Regenerative medicine Medium 34188056
2021 SMAD4 represses FOSL1 expression, and FOSL1 is sufficient to drive metastatic colonization to the lung as identified in an in vivo genetic screen using isogenic SMAD4-deleted pancreatic cancer cell lines. Isogenic SMAD4 cell lines, in vivo metastasis screen, FOSL1 overexpression Cell reports Medium 34320363
2022 FOSL1 binds to the Klotho promoter (demonstrated by ChIP enrichment) and preserves Klotho expression during acute kidney injury. Selective Fosl1 deficiency in proximal tubular cells (Fosl1Δtub) worsens AKI, reduces Klotho, and increases NF-κB/AP-1 activity; recombinant Klotho administration rescues Fosl1Δtub mice from cisplatin-AKI, placing Klotho downstream of Fosl1. ChIP (Fosl1 binding to Klotho promoter), conditional tubular-specific Fosl1 KO mice, cisplatin/folate AKI models, recombinant Klotho rescue Kidney international High 36565807
2022 FOSL1 and FOSL2 co-repress Th17 fate-specification in human T cells, contrasting with BATF which promotes the Th17 lineage. Genome-wide binding analysis revealed FOSL1, FOSL2, and BATF share occupancy over regulatory regions of Th17 commitment genes and share protein-interacting partners, suggesting a competitive mechanism. Genome-wide ChIP-seq binding analysis, siRNA-mediated knockdown, Th17 differentiation assay, protein interaction mapping Nucleic acids research Medium 35511484
2022 FOSL1 positively regulates DUSP7 transcription in doxorubicin-resistant breast cancer cells, and DUSP7 promotes dephosphorylation of PEA15, enhancing drug resistance. This FOSL1/DUSP7/PEA15 pathway was established by ChIP (FOSL1 binding to DUSP7 promoter) and functional rescue experiments. ChIP (FOSL1 binding to DUSP7 promoter), siRNA knockdown, overexpression, in vitro and in vivo drug resistance assays Molecular cancer research Medium 34907034
2022 FOSL1 deacetylation at Lys-116 within its DNA binding domain increases its transcriptional activity. TRPM7 induces FOSL1 transcriptional activation via STAT3, which binds to GAS elements at -328 to -336 and -378 to -386 in the FOSL1 promoter (confirmed by ChIP-qPCR). FOSL1 promotes glioma stem cell marker expression and maintains stem cell activity. Luciferase reporter with GAS element mutants, ChIP-qPCR, constitutively active/dominant-negative STAT3, FOSL1 acetylation/deacetylation assay Cellular and molecular life sciences Medium 37642779
2023 CYTOR (a nuclear lncRNA) facilitates formation of FOSL1 phase-separated condensates and FOSL1-dependent super-enhancers to drive cancer stemness and pro-metastatic gene expression in HNSCC tumor budding cells. In turn, FOSL1 activation promotes CYTOR transcription, forming a feedback loop. Depletion of CYTOR disrupts FOSL1-dependent SEs. Phase separation assay, ChIP-seq for SE analysis, CYTOR/FOSL1 knockdown, in vivo tumor growth and lymph node metastasis model Advanced science Medium 38032139
2023 CAF-derived exosomal FOSL1 is transferred to colorectal cancer cells and transcriptionally activates ITGB4 (integrin β4), promoting CRC cell proliferation, stemness, and oxaliplatin resistance. Transcriptional activation of ITGB4 by FOSL1 was confirmed by ChIP and dual-luciferase reporter assays. Exosome isolation, ChIP assay, dual-luciferase reporter assay, FOSL1 overexpression/knockdown, co-culture with CAF-conditioned medium, exosome inhibitor GW4869 Molecular and cellular biochemistry Medium 37160555
2025 FOSL1 transcriptionally activates glycolytic genes SLC2A1, ENO1, and LDHA in TNBC cells, enhancing the Warburg effect. FOSL1 promotes tumor growth in a glycolysis-dependent manner (2-DG abolishes FOSL1 oncogenic effects). Established by ChIP and luciferase reporter assays. ChIP, luciferase reporter assay, glucose uptake/lactate/ECAR measurements, 2-DG inhibition, xenograft model Journal of translational medicine Medium 39748430

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen. Molecular and cellular biology 573 3133553
2000 Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nature genetics 279 10655067
2012 MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene 191 23001043
2010 Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages. Cell research 183 20386569
1998 Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Molecular and cellular biology 170 9819396
1995 Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron. Molecular and cellular biology 160 7791782
2014 Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression. Cell death and differentiation 131 25301070
2009 Phosphate-dependent regulation of MGP in osteoblasts: role of ERK1/2 and Fra-1. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 122 19419315
2006 Fra-1 a target for cancer prevention or intervention. Gene 109 16784822
2002 Transactivation of Fra-1 and consequent activation of AP-1 occur extracellular signal-regulated kinase dependently. Molecular and cellular biology 106 11756554
2003 Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway. Genes to cells : devoted to molecular & cellular mechanisms 90 12622723
2003 Accumulation of Fra-1 in ras-transformed cells depends on both transcriptional autoregulation and MEK-dependent posttranslational stabilization. Molecular and cellular biology 89 12773579
2021 FOSL1 promotes metastasis of head and neck squamous cell carcinoma through super-enhancer-driven transcription program. Molecular therapy : the journal of the American Society of Gene Therapy 87 33794365
2016 SIRT1 promotes epithelial-mesenchymal transition and metastasis in colorectal cancer by regulating Fra-1 expression. Cancer letters 84 26975631
2021 NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1. eLife 82 34399888
2022 Role of the Transcription Factor FOSL1 in Organ Development and Tumorigenesis. International journal of molecular sciences 78 35163444
2017 The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation. Oncogene 75 28481878
2007 Fra-1 and Stat3 synergistically regulate activation of human MMP-9 gene. Molecular immunology 71 17572495
2019 Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis. The Journal of clinical investigation 70 30990796
2022 FOSL1 promotes proneural-to-mesenchymal transition of glioblastoma stem cells via UBC9/CYLD/NF-κB axis. Molecular therapy : the journal of the American Society of Gene Therapy 67 35351656
2011 FOSL1 is integral to establishing the maternal-fetal interface. Molecular and cellular biology 67 21947281
2019 The stromal loss of miR-4516 promotes the FOSL1-dependent proliferation and malignancy of triple negative breast cancer. Cancer letters 63 31672492
2014 FRA-1 as a driver of tumour heterogeneity: a nexus between oncogenes and embryonic signalling pathways in cancer. Oncogene 63 25381818
2020 The nuclear oncoprotein Fra-1: a transcription factor knocking on therapeutic applications' door. Oncogene 62 32385348
2018 microRNA-130a suppresses breast cancer cell migration and invasion by targeting FOSL1 and upregulating ZO-1. Journal of cellular biochemistry 62 29384218
2017 Oncogenic K-Ras upregulates ITGA6 expression via FOSL1 to induce anoikis resistance and synergizes with αV-Class integrins to promote EMT. Oncogene 59 28604746
2013 Role of the AP-1 transcription factor FOSL1 in endothelial cells adhesion and migration. Cell adhesion & migration 56 24084233
2020 Silencing lncRNA AGAP2-AS1 Upregulates miR-195-5p to Repress Migration and Invasion of EC Cells via the Decrease of FOSL1 Expression. Molecular therapy. Nucleic acids 53 32199129
2011 Molecular characterization of the microRNA-138-Fos-like antigen 1 (FOSL1) regulatory module in squamous cell carcinoma. The Journal of biological chemistry 52 21969367
2022 The Fra-1/AP-1 Oncoprotein: From the "Undruggable" Transcription Factor to Therapeutic Targeting. Cancers 51 35326630
2003 Fra-1 targets the AP-1 site/2G single nucleotide polymorphism (ETS site) in the MMP-1 promoter. European journal of biochemistry 47 14519134
2017 MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells. Oncogenesis 46 28604765
2011 Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells. Biochimica et biophysica acta 46 21640141
2018 FOSL1 Promotes Kras-induced Lung Cancer through Amphiregulin and Cell Survival Gene Regulation. American journal of respiratory cell and molecular biology 45 29112457
2007 FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders. BMC cancer 45 17254320
2011 Elevated Fra-1 expression causes severe lipodystrophy. Journal of cell science 44 21486951
2000 FRA-1 expression in hyperplastic and neoplastic thyroid diseases. Clinical cancer research : an official journal of the American Association for Cancer Research 44 11106247
2021 FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted. Journal of hepatology 43 33887357
2020 EGFR-PKM2 signaling promotes the metastatic potential of nasopharyngeal carcinoma through induction of FOSL1 and ANTXR2. Carcinogenesis 43 31665243
2020 ETV4 is a theranostic target in clear cell renal cell carcinoma that promotes metastasis by activating the pro-metastatic gene FOSL1 in a PI3K-AKT dependent manner. Cancer letters 43 32305558
2016 The Fra-1-miR-134-SDS22 feedback loop amplifies ERK/JNK signaling and reduces chemosensitivity in ovarian cancer cells. Cell death & disease 43 27685628
2007 Ubiquitin-independent- versus ubiquitin-dependent proteasomal degradation of the c-Fos and Fra-1 transcription factors: is there a unique answer? Biochimie 43 17825471
2022 Melatonin inhibits EMT and PD-L1 expression through the ERK1/2/FOSL1 pathway and regulates anti-tumor immunity in HNSCC. Cancer science 42 35298069
2014 Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer. Nucleic acids research 41 25200076
2017 FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions. mBio 40 28049150
2021 SMAD4 represses FOSL1 expression and pancreatic cancer metastatic colonization. Cell reports 39 34320363
2012 Intermittent hypoxia and systemic leptin administration induces pSTAT3 and Fos/Fra-1 in the carotid body. Brain research 37 22364734
2006 A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression. The Journal of biological chemistry 37 16490785
2023 FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer. International journal of molecular sciences 35 37176013
2022 LncRNA HOTAIR sponges miR-301a-3p to promote glioblastoma proliferation and invasion through upregulating FOSL1. Cellular signalling 33 35292358
2012 Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo. PloS one 33 22911824
2022 The transcription factor Fosl1 preserves Klotho expression and protects from acute kidney injury. Kidney international 32 36565807
2021 FOSL1 promotes tumorigenesis in colorectal carcinoma by mediating the FBXL2/Wnt/β-catenin axis via Smurf1. Pharmacological research 32 33450386
2018 Integrin-uPAR signaling leads to FRA-1 phosphorylation and enhanced breast cancer invasion. Breast cancer research : BCR 32 29382358
2005 RPL38, FOSL1, and UPP1 are predominantly expressed in the pancreatic ductal epithelium. Pancreas 31 15714138
2022 A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation. Nucleic acids research 30 35511484
2021 Saikosaponin-d Alleviates Renal Inflammation and Cell Apoptosis in a Mouse Model of Sepsis via TCF7/FOSL1/Matrix Metalloproteinase 9 Inhibition. Molecular and cellular biology 30 34309413
2020 AR-induced long non-coding RNA LINC01503 facilitates proliferation and metastasis via the SFPQ-FOSL1 axis in nasopharyngeal carcinoma. Oncogene 30 32661324
2023 CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 38032139
2021 The role of FOSL1 in stem-like cell reprogramming processes. Scientific reports 28 34282187
2018 Inhibitor of Differentiation-1 Sustains Mutant KRAS-Driven Progression, Maintenance, and Metastasis of Lung Adenocarcinoma via Regulation of a FOSL1 Network. Cancer research 28 30563891
2010 Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. Oncogene 27 20543861
2002 Fra-1 substitutes for c-Fos in AP-1-mediated signal transduction in retinal apoptosis. Journal of neurochemistry 27 11953459
2022 NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation. Oncogene 26 34992218
2020 FOSL1 is a novel mediator of endotoxin/lipopolysaccharide-induced pulmonary angiogenic signaling. Scientific reports 26 32753701
2022 The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases. Frontiers in immunology 25 36032067
2020 Characterization of FosL1, a Plasmid-Encoded Fosfomycin Resistance Protein Identified in Escherichia coli. Antimicrobial agents and chemotherapy 25 31932373
1999 Fra-1 potentiates osteoclastic differentiation in osteoclast-macrophage precursor cell lines. Journal of cellular physiology 25 10199556
2016 HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells. Oncotarget 24 26734995
2011 Transcription factor Fra-1 induces cholangitis and liver fibrosis. Hepatology (Baltimore, Md.) 24 21480331
2022 Transcription Factor FOSL1 Enhances Drug Resistance of Breast Cancer through DUSP7-Mediated Dephosphorylation of PEA15. Molecular cancer research : MCR 23 34907034
2019 Fra-1 plays a critical role in angiotensin II-induced vascular senescence. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 30892941
2018 FOSL1 enhances growth and metastasis of human prostate cancer cells through epithelial mesenchymal transition pathway. European review for medical and pharmacological sciences 23 30575900
2023 Exosome-transmitted FOSL1 from cancer-associated fibroblasts drives colorectal cancer stemness and chemo-resistance through transcriptionally activating ITGB4. Molecular and cellular biochemistry 22 37160555
2021 Fosl1 is vital to heart regeneration upon apex resection in adult Xenopus tropicalis. NPJ Regenerative medicine 22 34188056
2012 Estrogen-induced expression of Fos-related antigen 1 (FRA-1) regulates uterine stromal differentiation and remodeling. The Journal of biological chemistry 22 22514284
2009 Fra-1/AP-1 impairs inflammatory responses and chondrogenesis in fracture healing. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 22 19558315
2025 FOSL1 transcriptionally dictates the Warburg effect and enhances chemoresistance in triple-negative breast cancer. Journal of translational medicine 21 39748430
2023 Influence of FOSL1 Inhibition on Vascular Calcification and ROS Generation through Ferroptosis via P53-SLC7A11 Axis. Biomedicines 21 36831172
2021 Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor. Cancer letters 21 33652085
2021 The Transcription Factor FRA-1/AP-1 Controls Lipocalin-2 Expression and Inflammation in Sepsis Model. Frontiers in immunology 21 34712224
2012 Rhinovirus-induced MMP-9 expression is dependent on Fra-1, which is modulated by formoterol and dexamethasone. Journal of immunology (Baltimore, Md. : 1950) 21 22461694
2024 FOSL1 regulates hyperproliferation and NLRP3-mediated inflammation of psoriatic keratinocytes through the NF-kB signaling via transcriptionally activating TRAF3. Biochimica et biophysica acta. Molecular cell research 20 38367916
2021 The long noncoding RNA GAS5 potentiates neuronal injury in Parkinson's disease by binding to microRNA-150 to regulate Fosl1 expression. Experimental neurology 20 34755654
2018 The expression analysis of Fra-1 gene and IL-11 protein in Iranian patients with ulcerative colitis. BMC immunology 20 29914371
2012 Genetic disruption of Fra-1 decreases susceptibility to endotoxin-induced acute lung injury and mortality in mice. American journal of respiratory cell and molecular biology 20 21816965
2007 Fra-1 governs cell migration via modulation of CD44 expression in human mesotheliomas. Molecular cancer 20 18096084
2021 FosL1 Is a Novel Target of Levetiracetam for Suppressing the Microglial Inflammatory Reaction. International journal of molecular sciences 19 34681621
2019 AP-1 Signaling by Fra-1 Directly Regulates HMGA1 Oncogene Transcription in Triple-Negative Breast Cancers. Molecular cancer research : MCR 19 31300541
2016 FOSL1 immunohistochemistry clarifies the distinction between desmoplastic fibroblastoma and fibroma of tendon sheath. Histopathology 19 27442992
2020 HOXA10 promotes the development of bladder cancer through regulating FOSL1. European review for medical and pharmacological sciences 18 32271412
2013 Expression profiling of genes regulated by Fra-1/AP-1 transcription factor during bleomycin-induced pulmonary fibrosis. BMC genomics 18 23758685
2023 TRPM7 transactivates the FOSL1 gene through STAT3 and enhances glioma stemness. Cellular and molecular life sciences : CMLS 17 37642779
2022 FRA-1: A key factor regulating signal transduction of tumor cells and a potential target molecule for tumor therapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 17 35658206
2018 Effects of FOSL1 silencing on osteosarcoma cell proliferation, invasion and migration through the ERK/AP-1 signaling pathway. Journal of cellular physiology 17 30471098
2009 Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses. International immunology 17 19251936
2023 ABCA1-Mediated EMT Promotes Papillary Thyroid Cancer Malignancy through the ERK/Fra-1/ZEB1 Pathway. Cells 16 36672209
2022 Fra-1 induces apoptosis and neuroinflammation by targeting S100A8 to modulate TLR4 pathways in spinal cord ischemia/reperfusion injury. Brain pathology (Zurich, Switzerland) 16 36634215
2016 Copy number and expression analysis of FOSL1, GSTP1, NTSR1, FADD and CCND1 genes in primary breast tumors with axillary lymph node metastasis. Cancer genetics 16 27388253
2011 Effects of expression of transcriptional factor AP-1 FOSL1 gene on psoriatic process. Bulletin of experimental biology and medicine 16 22235402

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