FOSL1 (FOS-like antigen 1)

2012-11-01   Senthilkumar B Rajamohan , Sekhar P Reddy 

Department of Medicine, Institute for Integrative Physiology, University of Chicago, Chicago, Illinois, USA (SBR); Department of Pediatrics, University of Illinois, Chicago, Illinois, USA (SPR)




Atlas Image
Transcriptional regulation of Fra-1 (Fosl-1): MAPK signaling activates transcriptional factors binding at the human Fra-1 promoter. Binding of Fra-1 and c-Jun to TRE sites of first intron regulates Fra-1 transcription. TRE - TPA response element, SRE - Serum response element, SRF - serum response factor, ATF - activating transcription factor binding site


Fra-1 (Fosl-1) is a basic leucine zipper (bZIP) transcription factor and a member of Fos family of proteins (Cohen and Curran, 1988). The Fra-1 gene spans about 8.31 kb including four exons and is located on chromosome 11q13. It contains two regulatory elements, an upstream 5-flanking region and an intragenic sequence, that are known to regulate its transcriptional induction (Verde et al., 2007). Two critical elements of the promoter, the upstream TPA response element (TRE) and the serum response element (SRE), are required for Fra-1 transcriptional induction in response to external stimuli, such as mitogens and cytokines (Adiseshaiah et al., 2003; Adiseshaiah et al., 2005). The intragenic regulatory element containing the TRE/TRE-like elements also contribute to Fra-1 induction (Bergers et al., 2005).


Fra-1 transcription is strongly inducible by mitogens and inflammatory cytokines as well by a wide variety of environmental toxicants, carcinogens, and pathogens. In contrast to the early activation of c-Jun and c-Fos (which peaks at 15-30 min), the induction of Fra-1 by various mitogenic and stressful stimuli peaks at 90-180 min, and this delayed induction is postulated to play important role in modulating the transcriptional response initiated by the AP-1 complex composed of Jun/c-Fos dimers. The Fra-1 promoter region contains a c-Fos-like serum response element (SRE), which is constitutively occupied by the serum response factor (SRF) and the ternary complex factor, Elk1. Recruitment of c-Jun to the upstream TRE and the presence of downstream SRE as well as the activating transcription factor (ATF) site are essential for Fra-1 induction by mitogenic and cytokine stimuli (Adiseshaiah et al., 2007). Sp1 family members also regulate Fra-1 transcription (Adiseshaiah et al., 2005). Other studies have shown that cis-elements, such as TRE and E boxes, located in the intragenic region also contribute to Fra-1 transcription (Bergers et al., 1995, Casalino et al., 2003,). Histone modifications, such as the phosphorylation of Histone 3 by PIM1 on the nucleasome at the MYC binding sites, regulate the transcriptional activation of Fra-1 (Zippo et al., 2007). In addition to transcriptional induction, ERK- dependent phosphorylation has been shown to play a key role in the protein stability and DNA binding activity of Fra-1 (Basbous et al., 2007, Young et al., 2002).


One pseudo gene is identified, the FOS-like antigen pseudogene, FOSL1P1 (NCBI, HGNC ID: 44055).


Atlas Image
A schematic diagram showing the modular structure of Fra-1 (1-271 AA). DBD -DNA binding domain, LZD - leucine-zipper domain, N - amino terminus, C - carboxyl terminus. P1 - Thr 231, P2 - Ser252, P3 - Ser265. In this, ERK mediated phosphorylation of serine residues 252 and 265 requires for the stabilization of Fra-1 in certain tumor cell lines (Basbous et al., 2007).


Fra-1 (Fosl-1) protein encodes for 271 amino acids with an expected molecular weight of 29.4 kDa. However, in immunoblot analysis of cellular extracts isolated from cells stimulated with growth factors or from cancer cells, Fra-1 exhibits multiple forms ranging from 30-40 kDa. The appearance of these multiple forms is mainly attributed to post-translational modification (e.g., phosphorylation) of this protein. Human and mouse Fra-1 exhibits 6 and 1 splice variants, respectively, and both exhibit one unspliced form. These different transcripts encode proteins with different functional domains. The functional significance of these alternatively spliced variants of Fra-1 for both in physiology and pathological processes remains unclear.


The expression of Fra-1 is high in smooth muscle cells, bronchial epithelial cells (trachea), and the pancreas, but its expression is low in other tissues, such as the brain and prostate.


Fra-1 (Fosl-1) contains a nuclear localization signal and is predominantly found in the nucleus. However, Fra-1 antigen is observed in the cytoplasm under certain conditions, such as elevated levels of oxidative stress (Burch et al., 2004) and in cancerous tissues (Song et al., 2006). Furthermore, a distinct cytoplasmic location of Fra-1 has been noted in non-small-cell lung cancer (Ma et al., 2009). Nuclear and cytoplasmic expression of Fra-1 is markedly elevated in human adenomas, adenocarcinomas and neuroendocrine carcinomas (Zhang et al., 2005).


After dimerization, mainly with the Jun or ATF family of proteins, Fra-1 binds to the TPA response element (TRE, or AP-1 site) and regulates gene expression in a context-dependent manner (Cohen et al., 1989). Fra-1 plays important roles in various biological processes, including inflammation, transformation, proliferation, and metastasis. Increased expression levels of Fra-1 is detectable in breast, lung, brain, colon and prostate cancers and its knockdown affects cancer cell progression (see below).


The Fra-1 gene is conserved in chimpanzee, dog, cow, mouse, rat, and Zebra fish.



No genetic mutations leading to activation or inactivation of this transcription factor in human disease development and in malignancies have been yet documented. Recently, the presence of SNPs was demonstrated in human Fra-1 (FOSL-1) gene, and these SNPs were shown to be associated with a decreased rate of lung function (Sandford et al., 2012).

Implicated in

Entity name
Thyroid cancer
Analysis of samples from thyroid cancer patients has shown an increase in Fra-1 protein expression in thyroid nodules (Chiappetta et al., 2000). Induction of Fra-1 expression has also been observed in human thyroid cancer cell lines (Battista et al., 1998). Inhibition of Fra-1 prevents the retrovirally induced neoplastic transformation of rat thyroid cells (Vallone et al., 1997). In thyroid cancer cells, Fra-1 binds to the cyclin A promoter and regulates its expression during cell-cycle progression (Casalino et al., 2007).
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Non-small-cell lung cancer (NSCLC)
Expression of AP-1 family proteins, and particularly Fra-1 has been detected in NSCLC cell lines (Risse-Hackl et al., 1998). Decreased levels of Fra-1 protein expression have been noted in the tumor tissue of non small cell lung cancer patients (Ma et al., 2009), and these decreased levels have been positively correlated with progression of tumor stage and worsening prognosis. Ectopic expression of Fra-1 in lung adenocarcinoma cells induces cancer. Interestingly, it has been reported that a DNA vaccine specific to Fra-1 prevents pulmonary cancer metastasis in syngeneic mice (Luo et al., 2005).
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Breast cancer
Increased expression of Fra-1 was observed in human breast cancer cells (Philips et al., 1998). Several studies have shown its involvement in cancer cell proliferation, motility and invasiveness (Bamberger et al., 1999; Belguise et al., 2005; Logullo et al., 2011). An increase in nuclear or cytoplasmic localization of Fra-1 has been considered as a marker of progression of breast cancer (Song et al., 2006, Chiappetta et al., 2007). Knockdown of Fra-1 in tumor associated macrophages with small interfering RNA has been found to significantly suppress the invasion, angiogenesis and metastasis of breast cancer tumor cells (Luo et al., 2010). Likewise, knockdown of Fra-1 in estrogen- resistant MCF-7 cells significantly affected their growth and enhanced their susceptibility to cell death in response to estrogen treatment (Pennanen et al., 2011). An increased accumulation of Fra-1 protein in estrogen-negative breast cancer cells is mediated through PKCθ pathway (Belguise et al., 2012). A mouse Fra-1 targeted DNA vaccine has been found to be effective in protection against breast cancer in mice (Luo et al., 2003). Low level of miRNA-34 has been correlated with an elevated level of Fra-1 expression in breast cancer tissues and cell lines, but ectopic miRNA-34 expression causes a down-regulation of Fra-1 levels and inhibits breast cancer cell progression (Yang et al., 2012). In a different study, Fra-1 overexpression was shown to increase the chemosensitive of breast cancer stem cells, suggesting Fra-1 can be considered as a prognostic responsive marker in breast cancer therapy (Lu et al., 2012).
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Bladder cancer
An increased level of Fra-1 expression is found in bladder tumor and cancer cell lines. Fra-1, via the transcriptional induction of the receptor tyrosine kinase AXL, promotes bladder cancer cell motility (Sayan et al., 2012).
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Colon cancer
Fra-1 and its dimeric partner, c-Jun, are up-regulated in human colorectal tumors (Zhang et al., 2005; Wang et al., 2002). In colon carcinoma cells, the basal induction and stabilization of Fra-1 has been shown to be regulated by ERK activity, and knockdown of Fra-1 suppresses colon cancer cell polarization and progression (Vial and Marshall, 2003). A potential role for Fra-1 in the regulation of vimentin during Ha-RAS-induced epithelial-to- mesenchymal transition and migration has been documented (Andreolas et al., 2008). By upregulating miR-34a, p53 indirectly down regulates Fra-1 mRNA and protein expression in colon cancer cells and inhibits cell migration and invasion (Wu et al., 2012).
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Prostate cancer
Akt signaling contributes to Fra-1 induction in the prostate cancer cells, mainly at the transcription level (Tiwari et al., 2003). An abnormal activation of Fra-1 has been linked to elevated expression levels of IL-6, which promote prostate cancer cell progression and resistance to chemotherapeutic agents (Zerbini et al., 2003).
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Esophageal squamous cell carcinoma (ESCC)
Immunoreactive analysis of two different ESCC cell lines (HKESC-1 and HKESC-2) derived from ESCC patients has demonstrated Fra-1 expression in these cell line (Hu et al., 2001). An elevated level of Fra-1expression is associated with poor prognosis of ESCC. Furthermore, Fra-1 knockdown in ESCC cell lines decreases tumor cell progression and invasion (Usui et al., 2012).
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Nasopharyngeal carcinoma (NPC)
Expression profiling of nasopharyngeal carcinoma and normal cells has revealed elevated expression levels of Fra-1 in NPC cancer cells (Fung et al., 2000). Fra-1 has been shown to play an important role in controlling latent membrane protein 2A (LMP2A)-induced NPC epithelial cell motility and invasiveness (Lan et al., 2012). Either inhibition of Fra-1 induction or suppression of ERK1 and ERK2 activation will block the LMP2A-induced MMP-9 expression required for cancer cell progression.
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Ectopic Fra-1 expression in malignant glioma cells leads to phenotypic changes associated with invasiveness and tumorigenicity (Debinski and Gibo, 2005). In contrast, knock down of Fra-1 in high-grade glioma (HGG) cells alters the morphology, reduces both anchorage-independence and tumorigenic potential (Debinski and Gibo, 2011). In rat C6 glioma cells, Fra-1 overexpression suppresses their proliferation rate and tumorogenic potential and promotes cellular apoptosis (Shirsat and Shaikh., 2003).
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Head and neck squamous cell carcinoma (HNSCC)
Analysis of the tumor samples from patients with head and neck squamous cell carcinomas (HNSCC) has shown an increase in Fra-1 mRNA expression when compared to matched adjacent mucosa samples. Furthermore, tumor tissue staining for Fra-1 in tumor tissues is intensely more reactive immunoreactive than that of adjacent normal tissue (Mangone et al., 2005).
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Fra-1 transgenic mice have been shown to be prone to developing biliary hepatic fibrosis, and Fra-1 has been associated with ductular proliferation and infiltration of inflammatory cells (Kireva et al., 2011). On the other hand, it negatively regulates pulmonary fibrosis (Rajasekaran et al., 2012). Genetic disruption of Fra-1 causes increased levels of inflammation, collagen accumulation, and profibrotic and fibrotic gene expression following bleomycin treatment when compared to wild-type Fra-1.
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Genetic disruption of Fos leads to osteopetrosis in mice (Matsuo et al., 2000). However, over expression of Fra-1 rescues this phenotype in c-Fos mutant mice. Rankl, an osteoclast differentiation factor, has been reported to induce Fra-1 expression in a c-Fos-dependent manner, suggesting the involvement of c-Fos-RANKL-Fra-1 signaling in osteoclast differentiation. It has also been reported that overexpression of Fra-1 in mice increases bone mass up to 5-fold compared to wild-type mice (Roschger et al., 2004).
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Acute lung injury and Sepsis
Increased expression of Fra-1 has been reported in lung epithelial cell of acute respiratory syndrome patients (Fudala et al., 2011). Mice lacking Fra-1 show decreased levels of acute lung injury and inflammation as well as increased survival following endotoxin (LPS) treatment when compared to their wild-type counterparts (Vaz et al., 2012); this improvement was associated with diminished and increased levels of NF-kB and c-Jun/AP-1 binding, respectively. In agreement with this result, mice overexpressing Fra-1 were shown in another study to have enhanced susceptibility to endotoxin-induced death (Takada et al., 2011).


Pubmed IDLast YearTitleAuthors
176166772007FRA-1 proto-oncogene induces lung epithelial cell invasion and anchorage-independent growth in vitro, but is insufficient to promote tumor growth in vivo.Adiseshaiah P et al
180982842008Fra-1 regulates vimentin during Ha-RAS-induced epithelial mesenchymal transition in human colon carcinoma cells.Andreolas C et al
105027341999Expression pattern of the AP-1 family in breast cancer: association of fosB expression with a well-differentiated, receptor-positive tumor phenotype.Bamberger AM et al
173718472007Ubiquitin-independent proteasomal degradation of Fra-1 is antagonized by Erk1/2 pathway-mediated phosphorylation of a unique C-terminal destabilizer.Basbous J et al
96905191998Increase in AP-1 activity is a general event in thyroid cell transformation in vitro and in vivo.Battista S et al
222867592012The PKCθ pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells.Belguise K et al
77917821995Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron.Bergers G et al
151431652004An extracellular signal-regulated kinase 1- and 2-dependent program of chromatin trafficking of c-Fos and Fra-1 is required for cyclin D1 expression during cell cycle reentry.Burch PM et al
173476532007Fra-1 promotes growth and survival in RAS-transformed thyroid cells by controlling cyclin A transcription.Casalino L et al
172543202007FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders.Chiappetta G et al
31335531988fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen.Cohen DR et al
24970531989The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes.Cohen DR et al
210884992011Fos-related antigen 1 (Fra-1) pairing with and transactivation of JunB in GBM cells.Debinski W et al
215269632011Increased levels of nuclear factor κB and Fos-related antigen 1 in lung tissues from patients with acute respiratory distress syndrome.Fudala R et al
109468522000Differential gene expression in nasopharyngeal carcinoma cells.Fung LF et al
114897942001Identification of differentially expressed genes in esophageal squamous cell carcinoma (ESCC) by cDNA expression array: overexpression of Fra-1, Neogenin, Id-1, and CDC25B genes in ESCC.Hu YC et al
214803312011Transcription factor Fra-1 induces cholangitis and liver fibrosis.Kireva T et al
225143482012Epstein-Barr virus latent membrane protein 2A promotes invasion of nasopharyngeal carcinoma cells through ERK/Fra-1-mediated induction of matrix metalloproteinase 9.Lan YY et al
213710802011Role of Fos-related antigen 1 in the progression and prognosis of ductal breast carcinoma.Logullo AF et al
225860642012Fra-1 promotes breast cancer chemosensitivity by driving cancer stem cells from dormancy.Lu D et al
158338772005A DNA vaccine targeting Fos-related antigen 1 enhanced by IL-18 induces long-lived T-cell memory against tumor recurrence.Luo Y et al
199668542010The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression.Luo YP et al
191601072009Expression and significance of FRA-1 in non-small-cell lung cancer.Ma K et al
160455422005Overexpression of Fos-related antigen-1 in head and neck squamous cell carcinoma.Mangone FR et al
106550672000Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation.Matsuo K et al
215704212011Inhibition of FOSL1 overexpression in antiestrogen-resistant MCF-7 cells decreases cell growth and increases vacuolization and cell death.Pennanen PT et al
96584021998FRA-1 expression level modulates regulation of activator protein-1 activity by estradiol in breast cancer cells.Philips A et al
229118242012Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo.Rajasekaran S et al
151210082004Normal mineralization and nanostructure of sclerotic bone in mice overexpressing Fra-1.Roschger P et al
226932722012NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease.Sandford AJ et al
218223092012Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL.Sayan AE et al
145974112003Overexpression of the immediate early gene fra-1 inhibits proliferation, induces apoptosis, and reduces tumourigenicity of c6 glioma cells.Shirsat NV et al
171922002006An association of a simultaneous nuclear and cytoplasmic localization of Fra-1 with breast malignancy.Song Y et al
214608582011Interstitial lung disease induced by gefitinib and toll-like receptor ligands is mediated by Fra-1.Takada Y et al
126922672003Gene expression profiling in prostate cancer cells with Akt activation reveals Fra-1 as an Akt-inducible gene.Tiwari G et al
220281132012The molecular role of Fra-1 and its prognostic significance in human esophageal squamous cell carcinoma.Usui A et al
93119911997Neoplastic transformation of rat thyroid cells requires the junB and fra-1 gene induction which is dependent on the HMGI-C gene product.Vallone D et al
218169652012Genetic disruption of Fra-1 decreases susceptibility to endotoxin-induced acute lung injury and mortality in mice.Vaz M et al
179571432007Deciphering AP-1 function in tumorigenesis: fra-ternizing on target promoters.Verde P et al
146253892003Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells.Vial E et al
122099532002Elevated protein expression of cyclin D1 and Fra-1 but decreased expression of c-Myc in human colorectal adenocarcinomas overexpressing beta-catenin.Wang HL et al
221982132012MicroRNA-34a inhibits migration and invasion of colon cancer cells via targeting to Fra-1.Wu J et al
230010432013MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1.Yang S et al
117565542002Transactivation of Fra-1 and consequent activation of AP-1 occur extracellular signal-regulated kinase dependently.Young MR et al
127278412003Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer.Zerbini LF et al
159231592005Differential expression of the AP-1 transcription factor family members in human colorectal epithelial and neuroendocrine neoplasms.Zhang W et al
176431172007PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation.Zippo A et al

Other Information

Locus ID:

NCBI: 8061
MIM: 136515
HGNC: 13718
Ensembl: ENSG00000175592


dbSNP: 8061
ClinVar: 8061
TCGA: ENSG00000175592


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Wnt signaling pathwayKEGGko04310
Wnt signaling pathwayKEGGhsa04310
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
198745742009Genetical genomic determinants of alcohol consumption in rats and humans.93
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
230010432013MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1.83
156086752005FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells.73
271341672016Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling.65
234830552013Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis.58
221982132012MicroRNA-34a inhibits migration and invasion of colon cancer cells via targeting to Fra-1.52
181722712008Interleukin-13 receptor alpha 2, EphA2, and Fos-related antigen 1 as molecular denominators of high-grade astrocytomas and specific targets for combinatorial therapy.49
257501732015Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition.43
156157162005MEK1-dependent delayed expression of Fos-related antigen-1 counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in response to cytokines or growth factors.37


Senthilkumar B Rajamohan ; Sekhar P Reddy

FOSL1 (FOS-like antigen 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-11-01

Online version: