Disease relevance of FOSL1

• FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells [1].
• We show that the DNA-binding activity of bacterially expressed trpE-Jun fusion proteins is increased many-fold upon their interaction with Fos (or a Fos-related antigen) expressed from a baculovirus vector [2].
• METHODS: We performed Western blot experiments with specific antibodies for each of the AP-1 proteins (c-jun, junB, junD, c-fos, fosB, fra-1, fra-2) with 41 endometrial carcinomas [3].
• Fos-related antigen 1 modulates malignant features of glioma cells [4].
• We found previously that a c-fos-inducible vascular endothelial growth factor D is ubiquitously up-regulated in HGG grade IV, glioblastoma multiforme, and that glioblastoma multiforme overexpress Fos-related antigen 1 (Fra-1) rather than the c-Fos [4].

High impact information on FOSL1

• The 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 [5].
• We identified Fosl1, one of the immediate-early genes, as a target of this signaling pathway [6].
• The direct interaction of the beta-catenin-T cell-factor/lymphoid-enhancer-factor complex with the promoter region of c-jun and fra-1 was shown in a gel shift assay [7].
• Overexpression of cDNA derived combinations of the nuclear proteins Jun and Fos or Jun and Fra1 repressed hARE-mediated chloramphenicol acetyltransferase (CAT) gene expression in transfected human hepatoblastoma (Hep-G2) cells [8].
• The levels of two other immediate-early genes, fosb and c-jun, also increased transiently after fibroblast contraction, whereas the levels of fra-1, fra-2, c-myc, and the transcription factor NF-kappaB remained the same, indicating that fibroblast contraction caused changes in a selective group of genes [9].

Chemical compound and disease context of FOSL1

• FRA-1 expression level modulates regulation of activator protein-1 activity by estradiol in breast cancer cells [10].

Biological context of FOSL1

• Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements [11].
• Interestingly, the -283 to +32 bp FRA-1 promoter fragment containing an SRE and an ATF site alone was also insufficient to confer TPA sensitivity to a reporter gene [11].
• Thus, a bipartite enhancer formed by an upstream TRE and the downstream SRE and ATF sites and the cognate factors is necessary and sufficient for the regulation of FRA-1 in response to mitogens [11].
• The Fos related antigen-1 (Fra-1) is activated in multiple cancers and gene ablation can suppress the invasive phenotypes of many tumor cell lines [12].
• Multiple cis-elements mediate the transcriptional activation of human fra-1 by 12-O-tetradecanoylphorbol-13-acetate in bronchial epithelial cells [13].

Anatomical context of FOSL1

• Human T-cell leukemia virus type 1 Tax activates transcription of the human fra-1 gene through multiple cis elements responsive to transmembrane signals [14].
• Ectopic Fra-1 induced prominent phenotypic changes in all three malignant glioma cell lines examined: H4, U-87 MG, and A-172 MG [4].
• RPL38, FOSL1, and UPP1 are predominantly expressed in the pancreatic ductal epithelium [15].
• Four proteins (FBR-v-Fos, FBJ-v-Fos, c-Fos, and FosB) transform established rodent fibroblast cell lines, while three (FosB2, Fra1, and Fra2) do not [16].
• Moreover, induction of c-fos resulted in the concomitant increase in the expression of fra-1 and c-jun, further highlighting the importance of AP-1 transcription factors in chondrocyte differentiation [17].

Associations of FOSL1 with chemical compounds

• As a further step, we have investigated whether bilberries and quercetin have the ability to induce transcription of Fos-related antigen 1 (Fra-1), which contains two EpREs in its promoter [18].
• Thrombin but not carbachol also induces a late increase in fra-1 mRNA, which peaks at 12 h [19].
• Treatment of cells with LY294002, an inhibitor of the PI3K-Akt pathway, completely blocked CS-induced FRA-1 expression [20].
• Irrespective of enhanced c-fos expression, c-jun was phosphorylated and became primarily heterodimerized with fra-1, which was also induced after PDTC incubation [21].
• Most interestingly, curcumin can reverse the expression dynamics of c-fos and fra-1 in this tumorigenic cell line, mimicking the expression pattern observed in normal controls or precancerous lesions [22].

Physical interactions of FOSL1

• Syk interacts with transcription factor Sp1 at the Sp1 DNA-binding site in the FRA1 promoter to repress Sp1-activated FRA1 transcription [23].
• The AP-1 sequence specifically bound to fra-1, junD, and junB in H441 lung adenocarcinoma nuclear extracts [24].

Regulatory relationships of FOSL1

• In contrast, Fra-1 strongly inhibits inducible IL-8 transcription [25].
• Analyses of AP-1 composition revealed that MCP-1 is only expressed in those cells where jun-family members were mainly heterodimerized with the fos-related protein fra-1 [26].
• Overexpression of fra1 in malignant cells significantly enhanced SPRR1B promoter activity [27].
• Transcription of the fos, fra-1 and fra-2 genes was induced by phorbol ester (TPA) stimulation of U937 human monocytic cells [28].
• Members of the AP1 family distinctly regulated the fra-1 promoter [13].

Other interactions of FOSL1

• Relative to c-Fos, the delayed recruitment of Fra-1 to the IL-8 promoter provides an example how AP-1 subunits may dampen excessive chemokine synthesis [25].
• PMA significantly induced binding of JunB and Fra1 in normal cells, while JunB and Fra2 bound to TREs in the malignant cells [27].
• In contrast, in tumorigenic cells the 1: 1 ratio between jun and fra-1 is disturbed and the MCP-1 gene is no longer expressed [26].
• FRA-1, a member of the FOS family of transcription factors, is overexpressed in a variety of human tumors, and contributes to tumor progression [11].
• Fra-1 activation involves its stabilization, ubiquitination, and interaction with histone deacetylase-1 [25].

Analytical, diagnostic and therapeutic context of FOSL1

• Chromatin immunoprecipitation assays revealed an enhanced recruitment of c-Jun, Jun-D, and Fra-2 to the endogenous fra-1 promoter upon TPA stimulation [13].
• Furthermore, Fra-1 transgene caused H4 cells, which do not form tumor xenografts, to regain tumorigenic capacity [4].
• Specific antibodies used in an electrophoretic mobility shift assay identified fra-1, fra-2, Jun D, and c-Jun proteins in the nuclear protein complex that bind a 51-mer containing the AP-1 consensus sequence at -184 and its flanking sequences in the uPAR promoter [29].
• The dissection of AP-1 composition in cervical-carcinoma cells revealed an inverse relationship between the Fos-related antigen Fra-1 and the tumorigenic phenotype [30].
• Immunoblotting was used to assess induction of the RARbeta, placental transforming growth factor beta (PTGF-beta), Fos-related antigen 1 (Fra-1), and transglutaminase II (TGase II) proteins by RA following treatment with azacitidine, a DNA demethylating agent [31].

References