Affinage

FOSL2

Fos-related antigen 2 · UniProt P15408

Length
326 aa
Mass
35.2 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOSL2 (Fra-2) is a leucine-zipper transcription factor that controls cell fate, differentiation, and fibrotic and oncogenic gene programs by forming AP-1 heterodimers with Jun-family partners and binding AP-1 and variant AP-1-related DNA sites (PMID:2110368, PMID:1945831). Its transcriptional output is partner- and context-dependent: Fra-2/c-Jun can suppress c-Jun-driven AP-1 activity while Fra-2/JunD activates transcription, with the suppressive difference mapping to the Fra-2 C-terminus (PMID:1945831, PMID:8415709). A central regulatory switch is ERK/MAP-kinase phosphorylation of multiple C-terminal Ser/Thr residues, which converts Fra-2 from a weak into an active transactivator and increases its DNA-binding activity (PMID:8058317, PMID:9188858, PMID:10359014); phosphorylation also governs Fra-2 protein stability, and MEKK1 directs Fra-2 ubiquitination and proteasomal turnover to set AP-1 complex composition (PMID:15558021, PMID:23807221). Fra-2 sustains its own expression through a delayed autoregulatory loop acting on AP-1/CRE-like sites in the fra-2 promoter (PMID:7862446, PMID:9188858). Through these mechanisms FOSL2 directly activates or represses defined targets — LIF in osteoclasts (PMID:18548006), CCR4 and a SOX4→HDAC8 cascade in adult T-cell leukemia (PMID:18071306, PMID:23482931), Foxo1 and Irf4 in B-cell development (PMID:28566276), Wnt5a in cancer-associated fibroblasts (PMID:33754039), SGK1 and SNAI2 in fibrosis and EMT (PMID:37662889, PMID:31807006), CCL28 in pancreatic cancer (PMID:37380804), and Rgs4, which it represses by dismissing the co-activator CBP from a variant AP-1R site (PMID:21367864). Functionally it controls osteoblast differentiation (PMID:8828501), osteoclast size (PMID:18548006), B-cell development (PMID:28566276), represses regulatory T-cell and Th17 fates (PMID:32610127, PMID:35511484), reprograms tumor-associated macrophages downstream of β-catenin (PMID:32548260), directs airway secretory-cell fate conversion via an IL-1β–Notch axis (PMID:34475534), and drives TGF-β-linked cardiac, pulmonary and renal fibrosis through autophagy and Smad cooperation (PMID:25375657, PMID:33668422, PMID:37662889). A c-Jun/Fra-2 dimer is sufficient to drive hepatocellular carcinoma through direct activation of a c-Myc 3' enhancer (PMID:38657045).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1990 High

    Established that Fra-2 is a functional c-Fos-like factor by showing it physically partners with c-Jun and is oncogenically transforming, defining it as an AP-1 component rather than an orphan immediate-early gene product.

    Evidence Co-immunoprecipitation and retroviral transformation in chicken embryo fibroblasts

    PMID:2110368

    Open questions at the time
    • Did not define which Jun partners predominate physiologically
    • No direct target genes identified
  2. 1991 High

    Resolved that Fra-2's transcriptional sign is determined by its Jun partner — Fra-2/c-Jun suppresses while Fra-2/JunD activates AP-1-site transcription — and localized the suppressive activity to the C-terminal half.

    Evidence In vitro heterodimer/DNA-binding assays and chimeric-protein reporter assays in F9 cells

    PMID:1945831 PMID:8415709

    Open questions at the time
    • Molecular basis of C-terminal suppression not defined
    • Partner selection in vivo unaddressed
  3. 1999 High

    Defined the ERK/MAPK phosphorylation switch: phosphorylation of mapped C-terminal Ser/Thr residues converts Fra-2 from a weak to an active transactivator and increases DNA binding, linking growth-factor signaling to Fra-2 output and autoregulation.

    Evidence In vitro kinase assays, phosphopeptide mapping, site-directed mutagenesis, constitutively active MEK1, EMSA and reporter assays in fibroblasts

    PMID:10359014 PMID:1899576 PMID:8058317 PMID:9188858

    Open questions at the time
    • Did not establish which physiological stimuli engage each site
    • Structural consequence of phosphorylation unknown
  4. 1996 High

    Connected Fra-2 to tissue differentiation by showing Fra-2/JunD is the dominant osteoblast AP-1 complex and is required for osteocalcin expression and osteoblast/bone organization.

    Evidence EMSA, reporter assays and antisense loss-of-function in osteoblasts

    PMID:8828501

    Open questions at the time
    • Direct osteocalcin promoter occupancy by Fra-2 not shown by ChIP
    • In vivo genetic confirmation absent at this stage
  5. 2008 High

    Provided the first germline genetic definition of a Fra-2 in vivo program, identifying LIF as a direct Fra-2/c-Jun target controlling osteoclast survival and size through LIF/HIF1α/PHD2 signaling.

    Evidence Fra-2 and LIF knockout mice, direct promoter mapping, double-KO epistasis and Bcl-2 rescue

    PMID:18548006

    Open questions at the time
    • Partner usage at LIF promoter in other tissues unknown
    • Phosphorylation-dependence of LIF activation in vivo untested
  6. 2013 Medium

    Established Fra-2 as an oncogenic driver in adult T-cell leukemia by defining direct CCR4 and SOX4 activation and a downstream SOX4→HDAC8 cascade required for cell growth.

    Evidence siRNA knockdown, AP-1-site reporter assays, microarray and promoter analysis in ATL cells

    PMID:18071306 PMID:23482931

    Open questions at the time
    • Genome-wide ATL target set not mapped at this stage
    • Reciprocal feedback within the cascade undefined
  7. 2013 Medium

    Linked Fra-2 to TGF-β/fibrotic signaling by showing it cooperates with Smad3 (promoting P300 recruitment and Smad3 acetylation) and with JunB at composite AP-1/Smad enhancers in an ERK-phosphorylation-dependent manner.

    Evidence Co-IP, acetylation and migration assays in NSCLC; ChIP, mutagenesis and ERK inhibition for LOXL4 enhancer

    PMID:23572561 PMID:25375657

    Open questions at the time
    • Direct Fra-2–P300 contacts not mapped
    • Generality of Smad3 cooperation across fibrotic genes untested
  8. 2011 High

    Demonstrated a repressive transcriptional mechanism: Fra-2 binds a variant AP-1-related (AP-1R) site at Rgs4 and represses transcription by dismissing the co-activator CBP, broadening the set of DNA elements and outputs Fra-2 controls.

    Evidence Dominant-negative Fra-2 transgenic rat profiling, ChIP, EMSA, promoter mutagenesis and CBP co-occupancy analysis

    PMID:21367864

    Open questions at the time
    • Mechanism of CBP dismissal not resolved
    • Generality of AP-1R-mediated repression unknown
  9. 2017 High

    Defined Fra-2's direct genome-wide program in lymphocyte development, showing it binds and activates Foxo1 and Irf4 to drive B-cell development, with these targets sufficient to rescue Fra-2 loss.

    Evidence Conditional knockout, ChIP-seq, expression profiling and Foxo1/Irf4 rescue in pro-B cells

    PMID:28566276

    Open questions at the time
    • Jun partner at these loci not specified
    • Upstream signal controlling Fra-2 in B cells undefined
  10. 2020 High

    Positioned Fra-2 as a repressor of immunosuppressive T-cell fates and a node in tumor immune regulation, repressing Treg development cell-intrinsically and acting downstream of β-catenin to drive M2-like macrophage polarization.

    Evidence Fosl2 transgenic/conditional KO mice, T-cell transfer and EAE models; macrophage-specific β-catenin ablation with transcriptomics in tumor models

    PMID:32548260 PMID:32610127

    Open questions at the time
    • Direct FoxP3-locus targets of Fra-2 not fully mapped
    • Mechanism of β-catenin→FOSL2 induction undefined
  11. 2021 High

    Identified Fra-2 as an instructive fate-conversion factor and angiogenic/fibrotic effector, required for IL-1β–Notch-driven secretory-to-AT2 conversion, for autophagy-coupled cardiac fibrosis, and for direct Wnt5a activation in cancer-associated fibroblasts.

    Evidence Lineage tracing and Notch manipulation in airway; conditional KO and Ang-II model with autophagy markers in cardiac fibroblasts; ChIP/reporter and angiogenesis assays in breast CAFs

    PMID:33668422 PMID:33754039 PMID:34475534

    Open questions at the time
    • Direct Fosl2 targets in alveolar conversion not enumerated
    • Mechanism of Fra-2/autophagy mutual regulation unresolved
  12. 2023 Medium

    Extended the direct fibrotic/immunosuppressive target repertoire and added m6A control, defining FOSL2→SGK1 in renal fibrosis, KRAS/MAPK→FOSL2→CCL28-driven Treg recruitment in pancreatic cancer, and METTL3-dependent m6A regulation of FOSL2 mRNA.

    Evidence ChIP and SGK1 rescue in renal models; CUT&Tag, ChIP-qPCR, reporter and multiomics in PDAC; MeRIP-seq and METTL3 knockdown in granulosa cells

    PMID:37179374 PMID:37380804 PMID:37662889

    Open questions at the time
    • Functional consequence of specific m6A sites on FOSL2 protein not mapped
    • Jun partner usage at SGK1/CCL28 not defined
  13. 2024 High

    Provided direct in vivo proof that a c-Jun/Fra-2 dimer is sufficient to cause cancer, driving hepatocellular carcinoma through a direct c-Myc 3' enhancer with oncogene addiction, and showed cofactor chromatin support via a RUNX1-NPM1 complex at FOSL2 ECM target loci.

    Evidence Hepatocyte c-Jun~Fra-2 fusion transgenic mice with enhancer ChIP, transgene switch-off and JQ-1 treatment; ChIP-seq/ATAC-seq and Co-IP in glioblastoma

    PMID:38286983 PMID:38657045

    Open questions at the time
    • Whether endogenous c-Jun/Fra-2 ratios reach oncogenic thresholds physiologically unknown
    • How RUNX1-NPM1 is recruited to FOSL2 loci unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How phosphorylation, partner choice, m6A modification, and cofactor context are integrated to flip FOSL2 between activator and repressor at individual loci genome-wide remains unresolved.
  • No unified model linking phospho-state to partner selection at specific targets
  • Structural basis of canonical vs AP-1R site discrimination unknown
  • Predictive rules for activation vs repression at a given promoter not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3
Partners
BATFEP300FOSL1JUNJUNBJUNDRUNX1SMAD3
Complex memberships
AP-1 (Fra-2/Jun heterodimer)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Fra-2 (FOSL2) protein forms a complex with c-Jun in cells, and overexpression of fra-2 causes transformation of chicken embryo fibroblasts, demonstrating shared biochemical functions with c-Fos. Co-immunoprecipitation in cells; retroviral overexpression transformation assay Proceedings of the National Academy of Sciences of the United States of America High 2110368
1991 Fra-2 forms stable heterodimers with c-Jun, JunB, or JunD in vitro; all complexes bind AP-1 sites. Unlike c-Fos/c-Jun (which activates), Fra-2/c-Jun suppresses c-Jun transactivation at AP-1 sites in F9 cells; this suppressive difference maps to the C-terminal half of Fra-2. Fra-2/JunD, however, activates transcription similarly to c-Fos/JunD. In vitro heterodimer formation assays; DNA-binding assays; transient transfection reporter assays; chimeric protein analysis Nucleic acids research High 1945831
1991 Fra-2 protein is phosphorylated on serine residues upon serum stimulation of chicken embryo fibroblasts, shifting it from hypophosphorylated (40–46 kDa) to a hyperphosphorylated 46 kDa form. Western blot with alkaline phosphatase treatment; metabolic labeling Biochemical and biophysical research communications Medium 1899576
1993 JunD mutants with transforming activity show enhanced transactivation specifically when heterodimerized with Fra-2 (but not c-Fos or Fra-1), indicating Fra-2 functions as a partner-specific transactivation enabler. Transient transfection reporter assay with AP-1 site in F9 cells; retroviral transformation assay in chicken embryo fibroblasts Proceedings of the National Academy of Sciences of the United States of America Medium 8415709
1994 Fra-2 is phosphorylated in vivo in a serum-dependent manner during G1 and in asynchronously growing Swiss 3T3 cells; MAP kinase (ERK) phosphorylates Fra-2 in vitro producing a gel-mobility shift similar to in vivo, and this phosphorylation increases Fra-2 DNA-binding activity. PKA, PKC, and cdc2 also phosphorylate Fra-2 in vitro but do not produce the same mobility shift. In vitro kinase assays (PKA, PKC, cdc2, MAP kinase); alkaline phosphatase treatment; 1D phosphopeptide mapping; EMSA DNA-binding assays Oncogene High 8058317
1995 Fra-2 mRNA and protein exhibit a circadian rhythm in the rat pineal gland (absent during the day, robustly increased at night), regulated by an adrenergic→cAMP mechanism; AP-1 binding activity in the pineal parallels Fra-2 protein levels. Immunoblot; Northern blot; organ culture with adrenergic/cAMP manipulations; EMSA The Journal of biological chemistry Medium 7592994
1995 Fra-2 protein binds AP-1 sites in the fra-2 promoter as a Fra-2/c-Jun complex; serum induction of fra-2 expression is mediated through CRE-like and AP-1 binding sites (not SRE); at late times post-stimulation, Fra-2/c-Jun re-occupies its own promoter, while at early times c-Fos/c-Jun drives fra-2 transcription, establishing a delayed autoregulatory loop. Promoter deletion/mutation reporter assays; EMSA with CEF nuclear extracts Oncogene Medium 7862446
1996 In fully differentiated osteoblasts, Fra-2 and JunD are the principal AP-1 complex members detectable, and co-expression of Fra-2/JunD (but not other Fos/Jun pairs) specifically stimulates osteocalcin promoter reporter expression in a site-specific manner; antisense suppression of Fra-2 impairs osteoblast differentiation and bone tissue-like organization. Western blot; EMSA; transient transfection reporter assays; promoter deletion analysis; antisense oligonucleotide suppression Endocrinology High 8828501
1997 In v-src-transformed chicken embryo fibroblasts, Fra-2 is extensively phosphorylated at multiple Ser and Thr residues in its C-terminal region (aa 266–323) by ERK2 (identified by in-gel kinase assay as a 42 kDa kinase); this phosphorylation converts Fra-2 from an inefficient into an active transactivator. Fra-2 promoter is autoregulated via AP-1 sites and a CRE-like sequence in response to Fra-2 phosphorylation status. In-gel kinase assay; site-directed mutagenesis of phosphorylation sites; Fra-2 C-terminal region as substrate; promoter reporter assays Oncogene High 9188858
1997 Exogenous Fra-2 expression represses AP-1 transcriptional activity in TPA-treated keratinocytes, whereas c-Fos activates it in calcium-treated cells, demonstrating opposing roles of Fra-2 and c-Fos in regulating AP-1 activity in keratinocytes. Transient transfection reporter assays; Western blot analysis of AP-1 protein expression Oncogene Medium 9315102
1998 Fra-2/JunD heterodimer specifically binds three AP-1 sites in the murine laminin alpha3A (lama3A) promoter and is required for TGF-β-responsive transcription; cooperative contribution of two distal AP-1 sites to TGF-β inducibility was established by mutagenesis. Site-directed mutagenesis of AP-1 sites; transient transfection reporter assays; EMSA (mobility shift assays) The Journal of biological chemistry High 9651314
1999 Phosphorylation of Fra-2 by MAP kinase (MAPK/MEK pathway) converts Fra-2 from a weak transactivator to an active one; MAPK phosphorylation sites were mapped by site-directed mutagenesis to three threonine and three serine residues in the C-terminal region, with threonines being more susceptible; a positive autoregulatory loop exists where phosphorylated Fra-2 drives fra-2 expression through AP-1 sites in the promoter. Site-directed mutagenesis of phosphorylation sites; constitutively active MEK1 cotransfection; reporter assays; transformation assays Cell growth & differentiation High 10359014
2001 Fra-2 expression in the rat pineal gland is required for circadian AP-1 binding activity and for expression of two specific target genes: type II iodothyronine deiodinase and nectadrin (CD24), identified by analysis of 1,190 genes in dominant-negative Fra-2 transgenic rats. Transgenic dominant-negative Fra-2 rat; gene expression profiling of 1,190 genes; targeted validation Molecular and cellular biology Medium 11340164
2001 NGF (but not EGF) specifically increases Fra-2 protein levels (particularly phosphorylated forms) and enhances Fra-2/JunD binding to AP-1 and CREB response elements in PC12 cells, correlating with NGF-specific differentiation vs. EGF-mediated mitogenesis; NGF elicits more sustained ERK phosphorylation than EGF. Gel mobility shift assays; supershift assays; Western blot; time-course ERK phosphorylation analysis The Journal of neuroscience Medium 11150315
2003 Fra-2 does not enhance cell motility when overexpressed in CSML0 adenocarcinoma cells (unlike Fra-1 or c-Fos), but antisense fra-2 knockdown in L929 fibroblastoid cells (which express Fra-1 and Fra-2) reduces motility, indicating Fra-2 contributes to but is not sufficient to drive motility and that this effect requires the cellular context of Fra-1 co-expression. Transfection of CSML0 cells with Fos family expression vectors; antisense knockdown; motility assays Oncogene Medium 12902987
2005 MEKK1 controls Fra-2 protein stability by inducing Fra-2 ubiquitination and proteasomal degradation; in MEKK1-/- cells, Fra-2 protein accumulates. MEKK1 thus regulates AP-1 complex composition by controlling Fra-2 turnover. MEKK1 knockout cells; ubiquitination assay; Western blot for Fra-2 protein levels Oncogene Medium 15558021
2007 Fra-2 is constitutively and aberrantly expressed in ATL cells; Fra-2/JunD heterodimer activates the CCR4 promoter via an AP-1 site; Fra-2 siRNA (but not JunB siRNA) reduces CCR4 expression and cell growth; Fra-2 drives expression of c-Myb, BCL-6, and MDM2. siRNA knockdown; transient transfection reporter assays; CCR4 promoter AP-1 site characterization; cell growth assays; microarray Oncogene High 18071306
2008 Fra-2 controls osteoclast survival and size by directly regulating LIF transcription (c-Jun co-factor); Fra-2-deficient mice develop giant osteoclasts with impaired LIF/LIF-receptor signaling; Fra-2 and LIF modulate HIF1alpha through transcriptional regulation of PHD2 (prolyl hydroxylase); placenta-specific Fra-2 drives hypoxia-dependent giant osteoclast formation. Fra-2 germline and conditional knockout mice; LIF knockout mice; LIF promoter identification as direct Fra-2/c-Jun target; PHD2 transcriptional regulation assay; Bcl-2 overexpression in vivo Nature High 18548006
2010 Fra-2 expression is upregulated in SSc fibroblasts by TGF-β and PDGF stimulation in an ERK-dependent manner; Fra-2 binds DNA of target genes in response to these stimuli; Fra-2 siRNA knockdown reduces collagen release from SSc fibroblasts stimulated with TGF-β or PDGF. siRNA knockdown; real-time PCR; immunohistochemistry; DNA binding assay; ERK inhibitor Arthritis and rheumatism Medium 20039427
2010 Fra-2 is induced in cardiac fibroblasts by hyperoxia/reoxygenation via an Ask-1-dependent mechanism; Ask-1 controls Fra-2 gene expression and nuclear localization; AP-1 sites in TGF-β1 and TGF-β3 promoters confer oxygen sensitivity; Fra-2 siRNA knockdown blunts O2-induced TGF-β1 and TGF-β3 expression. Fra-2 siRNA knockdown; Ask-1 siRNA; reporter assays with AP-1 site deletions; nuclear localization assay Cardiovascular research Medium 20427335
2011 FRA-2/FOSL2 selectively binds a variant AP-1-related (AP-1R) sequence (distinct from canonical AP-1 sites) in the Rgs4 proximal promoter to repress Rgs4 transcription; binding was confirmed by ChIP and EMSA; FRA-2-dependent repression involves dismissal of the co-activator CBP from the Rgs4 AP-1R sequence. Dominant-negative Fra-2 transgenic rat expression profiling; ChIP; EMSA; promoter mutagenesis; co-activator CBP co-occupancy analysis The Journal of biological chemistry High 21367864
2013 FOSL2 interacts with Smad3 in vitro and in vivo (co-IP); FOSL2 promotes P300 binding to Smad3 and P300-mediated acetylation of Smad3; this complex enhances TGF-β1-induced signaling and is required for TGF-β1-induced cell migration in NSCLC. Co-immunoprecipitation (in vitro and in vivo); P300 binding assay; Smad3 acetylation assay; migration assays with FOSL2 knockdown PloS one Medium 25375657
2013 TGF-β1 induces LOXL4 expression in aortic endothelial cells via functional cooperation between Smad proteins and a JunB/Fra-2 AP-1 complex; Fra-2 phosphorylation by ERK is required for this cooperation; a distal enhancer containing both an AP-1 site and a Smad binding element is absolutely required. Promoter deletion and mutagenesis; ChIP; co-transfection; ERK inhibitor treatment; LOXL4 functional assays Molecular and cellular biology Medium 23572561
2013 Fra-2 directly activates the SOX4 promoter via an AP-1 site together with JUND in ATL cells; SOX4 in turn directly activates the HDAC8 promoter, establishing a Fra-2/JUND → SOX4 → HDAC8 oncogenic cascade required for ATL cell growth. siRNA knockdown; reporter assay (AP-1 site in SOX4 promoter); microarray; HDAC8 promoter reporter assay Blood Medium 23482931
2013 Fra-2 expression is restricted to undifferentiated satellite cells and reserve cells in skeletal muscle (not in differentiated myofiber nuclei); Fra-2 silencing enhances myogenic differentiation markers; ERK1/2 signaling (cytokine-mediated) regulates Fra-2 protein stability via phosphorylation at S320 and T322 (identified by mass spectrometry and mutational analysis); S320 phosphorylation occurs transiently in activated satellite cells and is extinguished in differentiating cells. Fra-2 siRNA knockdown; mass spectrometry; site-directed mutagenesis of S320/T322; immunofluorescence in satellite cells; ERK1/2 signaling manipulation Cell death & disease High 23807221
2016 Fra-2 binds the TIMP-1 promoter (confirmed by ChIP) in monocytes; TLR-8 stimulation combined with histone demethylation (DZNep treatment) enhances Fra-2 and TIMP-1 expression; Fra-2-driven TIMP-1 production by monocytes induces transdifferentiation of dermal fibroblasts into myofibroblasts. ChIP; luciferase reporter assay; siRNA/inhibitor treatments; co-culture of monocytes and fibroblasts; TIMP-1 blocking antibody Arthritis & rheumatology Medium 26814616
2017 Fra-2 regulates B cell development by directly binding and enhancing transcription of Foxo1 and Irf4 (identified by ChIP-seq); deletion of Fra-2 reduces expression of Foxo1, Irf4, Ikaros, Aiolos, IL7Rα, and Rag1/2; exogenous Foxo1 and Irf4 fully rescue pro-B cell proliferation and small pre-B cell differentiation in Fra-2-deficient cells. Fra-2 conditional knockout; gene expression profiling; ChIP-seq; IL-7-stimulated pro-B cell cultures; Foxo1/Irf4 rescue experiments The Journal of experimental medicine High 28566276
2019 HGF/MET signaling induces phosphorylation and upregulation of FOSL2 via ERK1/2 kinase in NSCLC cells; FOSL2 binds the SNAI2 promoter and promotes SNAI2 transcription (confirmed by ChIP and dual-luciferase assay), driving EMT, invasion, and migration. Western blot for phospho-FOSL2; ERK1/2 manipulation; ChIP; dual-luciferase reporter assay; transwell/scratch assays OncoTargets and therapy Medium 31807006
2020 Fosl2 (Fra-2) is induced by TCR signaling in T cells and cell-intrinsically represses Treg development; Fosl2 overexpression reduces FoxP3 expression and other Treg differentiation genes; transfer of Fosl2tg T cells transfers inflammation, suppressible by co-delivery of Tregs; Fosl2 deficiency reduces EAE severity. Fosl2 transgenic and conditional knockout mice; Rag2-/- cross; T cell transfer experiments; EAE model; gene expression analysis Cell reports High 32610127
2020 β-catenin transcriptionally activates FOSL2 in tumor-associated macrophages (TAMs); FOSL2 drives a gene regulatory switch from M1-like to M2-like TAMs promoting immunosuppression; β-catenin ablation in macrophages reprograms M2 to M1 TAMs via FOSL2 suppression. Pharmacological and macrophage-specific genetic ablation of β-catenin; transcriptome analysis; in vitro TAM model; in vivo lung tumor models Science advances Medium 32548260
2021 FOSL2 in breast cancer-associated fibroblasts (CAFs) is regulated by estrogen/cAMP/PKA signaling; FOSL2 directly transcriptionally activates Wnt5a (confirmed by dual luciferase reporter and ChIP); Wnt5a secreted from CAFs activates FZD5/NF-κB/ERK signaling in endothelial cells to promote VEGF-independent angiogenesis. ChIP; dual luciferase reporter assays; FOSL2/Wnt5a siRNA knockdown; FOSL2 overexpression; tube formation/sprouting/xenograft assays; anti-VEGF blocking Theranostics High 33754039
2021 IL-1β signaling modulates Jag1/Jag2 expression in ciliated airway cells to inhibit Notch signaling in secretory cells, which activates Fosl2; Fosl2 is required for conversion of secretory cells to alveolar type 2 cells during alveolar regeneration, establishing an IL-1β–Notch–Fosl2 axis in secretory cell fate conversion. Genetic lineage tracing; Notch inhibition; Fosl2 gain- and loss-of-function; epigenetic signature analysis; human KDR+ secretory cell validation Nature cell biology High 34475534
2021 Fosl-2 (FOSL2) regulates autophagy in cardiac fibroblasts; Fosl-2 overexpression increases LC3BII, Beclin-1, and Atg5 levels; Fosl-2 silencing suppresses collagen, α-SMA, and Beclin-1; silencing LC3B or Beclin-1 reduces Fosl-2 in TGF-β-activated cells (mutual regulation); Fosl-2-deficient or Atg5-deficient stromal cells protect from angiotensin II-induced cardiac fibrosis in vivo. GapmeR antisense oligonucleotide silencing; Fosl-2tg cardiac fibroblasts; Ccl19Cre Fosl2flox/flox and Ccl19Cre Atg5flox/flox conditional KO mice; osmotic minipump angiotensin II model; immunohistochemistry International journal of molecular sciences High 33668422
2022 FOSL2 co-represses Th17 fate specification together with FOSL1 during human Th17 differentiation (opposite to BATF which promotes Th17); FOSL1, FOSL2, and BATF share genomic binding sites over Th17 lineage regulatory regions; they share protein-interacting partners; SNPs at FOSL2 binding sites alter its DNA binding capacity. siRNA knockdown of FOSL1/FOSL2/BATF; genome-wide ChIP-seq binding analysis; protein interaction studies; SNP binding assay; human Th17 differentiation cultures Nucleic acids research High 35511484
2023 FOSL2 binds the SGK1 promoter (confirmed by ChIP) and transcriptionally activates SGK1; in TGF-β1-induced renal tubular epithelial cells, FOSL2 silencing reduces SGK1 expression, and SGK1 overexpression rescues the anti-fibrotic effects of FOSL2 knockdown, placing FOSL2 upstream of SGK1 in renal fibrosis via EMT. ChIP; siRNA knockdown; TGF-β1-induced cell model; UUO mouse model; SGK1 overexpression rescue experiments; Western blot for EMT markers Journal of translational internal medicine Medium 37662889
2023 Butyric acid decreases FOSL2 m6A methylation and mRNA expression by suppressing METTL3 (an m6A methyltransferase) in granulosa cells; FOSL2 promotes NLRP3 inflammasome activation and IL-6/TNF-α expression; identified by RNA-seq and MeRIP-seq as a METTL3 target. RNA-seq; MeRIP-seq; butyric acid treatment; METTL3 siRNA; FOSL2 expression measurement; NLRP3/cytokine assays Clinical epigenetics Medium 37179374
2023 FOSL2 is a downstream target of the KRAS/MAPK pathway; FOSL2 directly binds the CCL28 promoter and transcriptionally activates CCL28 (confirmed by CUT&Tag and ChIP-qPCR + dual-luciferase reporter); CCL28 recruits regulatory T cells to drive immune suppression in pancreatic ductal adenocarcinoma. ATAC-seq, H3K27ac ChIP-seq, RNA-seq in GEMMs; CUT&Tag; ChIP-qPCR; dual-luciferase reporter; KRAS/MAPK pathway analysis; xenograft models British journal of cancer High 37380804
2024 A single-chain c-Jun~Fra-2 fusion protein (mimicking the c-Jun/Fra-2 AP-1 dimer) drives spontaneous hepatocellular carcinoma when expressed in hepatocytes; c-Myc is a direct transcriptional target of c-Jun/Fra-2 via a conserved distal 3' enhancer; tumors regress when the transgene is switched off (oncogene addiction); BET inhibitor JQ-1 targeting c-Myc reduces tumor growth. Hepatocyte-restricted c-Jun~Fra-2 transgenic mice; AP-1 enhancer ChIP for c-Myc 3' enhancer; transgene switch-off experiment; JQ-1 BET inhibitor treatment in vivo Proceedings of the National Academy of Sciences of the United States of America High 38657045
2024 RUNX1 interacts with NPM1 to maintain chromatin accessibility at FOSL2-regulated ECM gene loci; this RUNX1-NPM1 complex facilitates FOSL2-mediated transcriptional activation of ECM-related genes (FN1, COL4A1, LUM) in glioblastoma, independent of RUNX1's own transcriptional function. ChIP-seq; RNA-seq; Co-IP for RUNX1-NPM1 interaction; ATAC-seq for chromatin accessibility; functional ECM gene expression assays Cell death & disease Medium 38286983

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 Isolation and characterization of fra-2, an additional member of the fos gene family. Proceedings of the National Academy of Sciences of the United States of America 310 2110368
1991 Difference in transcriptional regulatory function between c-Fos and Fra-2. Nucleic acids research 209 1945831
2008 Identification of FRA1 and FRA2 as genes involved in regulating the yeast iron regulon in response to decreased mitochondrial iron-sulfur cluster synthesis. The Journal of biological chemistry 175 18281282
2009 The yeast iron regulatory proteins Grx3/4 and Fra2 form heterodimeric complexes containing a [2Fe-2S] cluster with cysteinyl and histidyl ligation. Biochemistry 168 19715344
1996 Developmental expression and activities of specific fos and jun proteins are functionally related to osteoblast maturation: role of Fra-2 and Jun D during differentiation. Endocrinology 165 8828501
2020 Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer. Science advances 162 32548260
2008 Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 153 18548006
2017 Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Annals of the rheumatic diseases 148 28814429
2019 lncRNA UCA1 Mediates Resistance to Cisplatin by Regulating the miR-143/FOSL2-Signaling Pathway in Ovarian Cancer. Molecular therapy. Nucleic acids 143 31234009
1994 Regulation of Fra-1 and Fra-2 phosphorylation differs during the cell cycle of fibroblasts and phosphorylation in vitro by MAP kinase affects DNA binding activity. Oncogene 138 8058317
2003 The cold-regulated transcriptional activator Cbf3 is linked to the frost-tolerance locus Fr-A2 on wheat chromosome 5A. Molecular genetics and genomics : MGG 122 12715154
1995 Differential expression of the fos and jun family members c-fos, fosB, Fra-1, Fra-2, c-jun, junB and junD during human epidermal keratinocyte differentiation. Oncogene 121 8545126
2004 The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas. Breast cancer research and treatment 111 15319566
2000 Regulation of AP1 (Jun/Fos) factor expression and activation in ovarian granulosa cells. Relation of JunD and Fra2 to terminal differentiation. The Journal of biological chemistry 106 10934195
2021 FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts. Theranostics 104 33754039
2018 miR-143-3p inhibits the proliferation, migration and invasion in osteosarcoma by targeting FOSL2. Scientific reports 95 29330462
1996 Transcription factor AP-1, and the role of Fra-2. Immunology and cell biology 94 8723999
2010 The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis and rheumatism 93 20039427
2020 The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development. Cell reports 89 32610127
2012 Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Annals of the rheumatic diseases 89 22523431
2000 High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model. Oncogene 86 10962557
1995 Circadian expression of transcription factor Fra-2 in the rat pineal gland. The Journal of biological chemistry 85 7592994
2019 lncRNA UCA1 Promotes Gefitinib Resistance as a ceRNA to Target FOSL2 by Sponging miR-143 in Non-small Cell Lung Cancer. Molecular therapy. Nucleic acids 84 31951852
2023 Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome. Clinical epigenetics 81 37179374
2013 LOXL4 is induced by transforming growth factor β1 through Smad and JunB/Fra2 and contributes to vascular matrix remodeling. Molecular and cellular biology 78 23572561
2005 The expression of several Cbf genes at the Fr-A2 locus is linked to frost resistance in wheat. Molecular genetics and genomics : MGG 77 16200412
2014 Copy number and haplotype variation at the VRN-A1 and central FR-A2 loci are associated with frost tolerance in hexaploid wheat. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 71 24626953
1995 Two activator protein-1 elements in the matrix metalloproteinase-1 promoter have different effects on transcription and bind Jun D, c-Fos, and Fra-2. Matrix biology : journal of the International Society for Matrix Biology 71 8785586
2008 Estrogen reduces aldosterone, upregulates adrenal angiotensin II AT2 receptors and normalizes adrenomedullary Fra-2 in ovariectomized rats. Neuroendocrinology 63 18679017
2007 Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia. Oncogene 63 18071306
2023 LncRNA ITGB2-AS1 promotes cisplatin resistance of non-small cell lung cancer by inhibiting ferroptosis via activating the FOSL2/NAMPT axis. Cancer biology & therapy 62 37370246
2021 Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration. Nature cell biology 62 34475534
1997 Opposing activities of c-Fos and Fra-2 on AP-1 regulated transcriptional activity in mouse keratinocytes induced to differentiate by calcium and phorbol esters. Oncogene 62 9315102
2003 Role of the Fos family members, c-Fos, Fra-1 and Fra-2, in the regulation of cell motility. Oncogene 60 12902987
2013 SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma. Blood 56 23482931
2019 Transcription factor Fra-2 and its emerging role in matrix deposition, proliferation and inflammation in chronic lung diseases. Cellular signalling 55 31473307
1997 Phosphorylation and high level expression of Fra-2 in v-src transformed cells: a pathway of activation of endogenous AP-1. Oncogene 54 9188858
2014 FOSL2 positively regulates TGF-β1 signalling in non-small cell lung cancer. PloS one 52 25375657
2021 SNHG17 promotes colorectal tumorigenesis and metastasis via regulating Trim23-PES1 axis and miR-339-5p-FOSL2-SNHG17 positive feedback loop. Journal of experimental & clinical cancer research : CR 51 34782005
2017 Copy number variations of CBF genes at the Fr-A2 locus are essential components of winter hardiness in wheat. The Plant journal : for cell and molecular biology 50 27859852
2001 Tissue-specific transgenic knockdown of Fos-related antigen 2 (Fra-2) expression mediated by dominant negative Fra-2. Molecular and cellular biology 50 11340164
2011 A role for katanin in plant cell division: microtubule organization in dividing root cells of fra2 and lue1Arabidopsis thaliana mutants. Cytoskeleton (Hoboken, N.J.) 48 21721142
2007 Restraint-induced fra-2 and c-fos expression in the rat forebrain: relationship to stress duration. Neuroscience 47 17936518
1999 Fra-2-positive autoregulatory loop triggered by mitogen-activated protein kinase (MAPK) and Fra-2 phosphorylation sites by MAPK. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 45 10359014
1994 Cloning and characterisation of the mouse fra-2 gene. Oncogene 45 7936655
2018 MiR-133a acts as an anti-oncogene in Hepatocellular carcinoma by inhibiting FOSL2 through TGF-β/Smad3 signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 44 30086463
2016 Copy number variation of CBF-A14 at the Fr-A2 locus determines frost tolerance in winter durum wheat. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 43 26883046
2007 Role of Fra-2 in breast cancer: influence on tumor cell invasion and motility. Breast cancer research and treatment 43 17393299
2023 FOSL2 participates in renal fibrosis via SGK1-mediated epithelial-mesenchymal transition of proximal tubular epithelial cells. Journal of translational internal medicine 42 37662889
1995 fra-2 promoter can respond to serum-stimulation through AP-1 complexes. Oncogene 42 7862446
2016 Histone Demethylation and Toll-like Receptor 8-Dependent Cross-Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra-2. Arthritis & rheumatology (Hoboken, N.J.) 41 26814616
1998 Three activator protein-1-binding sites bound by the Fra-2.JunD complex cooperate for the regulation of murine laminin alpha3A (lama3A) promoter activity by transforming growth factor-beta. The Journal of biological chemistry 41 9651314
1998 Expression of c-jun, junB, c-fos, fra-1 and fra-2 mRNA in the rat brain following seizure activity and axotomy. Brain research 40 9622645
1995 Tissue-specific expression of the fos-related transcription factor fra-2 during mouse development. Oncogene 40 7700631
2021 EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2. Cell death & disease 39 33712565
1996 Changes in the expression of transcription factors ATF-2 and Fra-2 after axotomy and during regeneration in rat retinal ganglion cells. Brain research. Molecular brain research 39 8883934
2017 miR-597 inhibits breast cancer cell proliferation, migration and invasion through FOSL2. Oncology reports 38 28393251
2010 Fra-2 mediates oxygen-sensitive induction of transforming growth factor beta in cardiac fibroblasts. Cardiovascular research 38 20427335
2001 Nerve growth factor, but not epidermal growth factor, increases Fra-2 expression and alters Fra-2/JunD binding to AP-1 and CREB binding elements in pheochromocytoma (PC12) cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 37 11150315
2017 Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription. The Journal of experimental medicine 36 28566276
1999 Aldosterone action: induction of p21(ras) and fra-2 and transcription-independent decrease in myc, jun, and fos. The American journal of physiology 36 10329965
2014 Fra2 is a co-regulator of Fep1 inhibition in response to iron starvation. PloS one 35 24897379
2001 Cholesterol sulfate stimulates involucrin transcription in keratinocytes by increasing Fra-1, Fra-2, and Jun D. Journal of lipid research 33 11254751
2001 Parathyroid hormone stimulates fra-2 expression in osteoblastic cells in vitro and in vivo. Endocrinology 33 11316763
2018 Fos-like antigen 2 (FOSL2) promotes metastasis in colon cancer. Experimental cell research 32 30114390
2020 Hsa_circ_0001869 promotes NSCLC progression via sponging miR-638 and enhancing FOSL2 expression. Aging 31 33221767
2018 MicroRNA-30e promotes hepatocyte proliferation and inhibits apoptosis in cecal ligation and puncture-induced sepsis through the JAK/STAT signaling pathway by binding to FOSL2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 29787988
2022 A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation. Nucleic acids research 30 35511484
2020 Circular RNA hsa_circ_0056836 functions an oncogenic gene in hepatocellular carcinoma through modulating miR-766-3p/FOSL2 axis. Aging 30 32048611
2005 MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability. Oncogene 30 15558021
1993 JunD mutants with spontaneously acquired transforming potential have enhanced transactivating activity in combination with Fra-2. Proceedings of the National Academy of Sciences of the United States of America 30 8415709
2020 Long Non-Coding RNA OIP5-AS1 Knockdown Enhances CDDP Sensitivity in Osteosarcoma via miR-377-3p/FOSL2 Axis. OncoTargets and therapy 29 32440152
2010 The transcription factor Fra-2 promotes mammary tumour progression by changing the adhesive properties of breast cancer cells. European journal of cancer (Oxford, England : 1990) 29 20226654
2021 The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis. International journal of molecular sciences 27 33668422
2019 HGF/MET Regulated Epithelial-Mesenchymal Transitions And Metastasis By FOSL2 In Non-Small Cell Lung Cancer. OncoTargets and therapy 27 31807006
2009 Cbf genes of the Fr-A2 allele are differentially regulated between long-term cold acclimated crown tissue of freeze-resistant and - susceptible, winter wheat mutant lines. BMC plant biology 27 19309505
2007 Simultaneous generation of fra-2 conditional and fra-2 knock-out mice. Genesis (New York, N.Y. : 2000) 27 17607691
1998 Overexpression of fra-2 in transgenic mice perturbs normal eye development. Oncogene 27 9764823
2024 Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc. Proceedings of the National Academy of Sciences of the United States of America 26 38657045
2018 MiR-124-3p suppresses glioma aggressiveness via targeting of Fra-2. Pathology, research and practice 26 30243808
2018 Fra2 Overexpression in Mice Leads to Non-allergic Asthma Development in an IL-13 Dependent Manner. Frontiers in immunology 25 30233597
2000 Circadian binding activity of AP-1, a regulator of the arylalkylamine N-acetyltransferase gene in the rat pineal gland, depends on circadian Fra-2, c-Jun, and Jun-D expression and is regulated by the clock's zeitgebers. Journal of neurochemistry 25 10987819
1991 Transcription of fra-2 mRNA and phosphorylation of Fra-2 protein are stimulated by serum. Biochemical and biophysical research communications 25 1899576
2024 RUNX1/NPM1/H3K4me3 complex contributes to extracellular matrix remodeling via enhancing FOSL2 transcriptional activation in glioblastoma. Cell death & disease 24 38286983
2020 HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2. Molecular therapy. Nucleic acids 24 33510945
2009 Aberrant selection and function of invariant NKT cells in the absence of AP-1 transcription factor Fra-2. Journal of immunology (Baltimore, Md. : 1950) 24 19620306
2019 MicroRNA (miR)-597-5p Inhibits Colon Cancer Cell Migration and Invasion by Targeting FOS-Like Antigen 2 (FOSL2). Frontiers in oncology 23 31245295
2012 Expression and function of FRA2/JUND in cutaneous T-cell lymphomas. Anticancer research 23 22493372
2020 Silencing circRNA_001937 may inhibit cutaneous squamous cell carcinoma proliferation and induce apoptosis by preventing the sponging of the miRNA‑597‑3p/FOSL2 pathway. International journal of molecular medicine 22 33000177
2023 Role of Fra-2 in cancer. Cell death and differentiation 21 38104183
2013 Signal-dependent fra-2 regulation in skeletal muscle reserve and satellite cells. Cell death & disease 21 23807221
2023 Chromatin accessibility uncovers KRAS-driven FOSL2 promoting pancreatic ductal adenocarcinoma progression through up-regulation of CCL28. British journal of cancer 20 37380804
2011 Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism. The Journal of biological chemistry 20 21367864
2023 SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis. Molecular cancer 18 36932385
2021 Mechanism of TCONS_00147848 regulating apoptosis of nasal mucosa cells and alleviating allergic rhinitis through FOSL2-mediated JAK/STAT3 signaling pathway. Scientific reports 18 34362948
2020 LncRNA LINC00313 Knockdown Inhibits Tumorigenesis and Metastasis in Human Osteosarcoma by Upregulating FOSL2 through Sponging miR-342-3p. Yonsei medical journal 18 32390359
2019 Role of linc00174/miR-138-5p (miR-150-5p)/FOSL2 Feedback Loop on Regulating the Blood-Tumor Barrier Permeability. Molecular therapy. Nucleic acids 18 31791014
1986 Fra(2) (q13) and inv(9) (p11q12) in autism: causal relationship? American journal of medical genetics 18 3953656
2020 Circ_0091581 Promotes the Progression of Hepatocellular Carcinoma Through Targeting miR-591/FOSL2 Axis. Digestive diseases and sciences 17 33040214
2019 Calcitonin gene‑related peptide regulates FOSL2 expression and cell proliferation of BMSCs via mmu_circRNA_003795. Molecular medicine reports 17 30896827

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