Disease relevance of Fosl1

• These studies suggest that inhibition of fra-1 signaling pathways may be a strategy for therapy of malignant mesothelioma [1].
• Overexpression of the immediate early gene fra-1 inhibits proliferation, induces apoptosis, and reduces tumourigenicity of c6 glioma cells [2].
• AP-1 DNA binding activity and the expression of a 35 kDa fos-related antigen (fra) remained elevated in the rat hippocampus for at least 2 weeks after a single systemic injection of kainate, which correlated with changes in gene expression during reactive gliosis [3].
• Using in situ hybridization, the expression of c-fos, fosB, fra-1, fra-2, c-jun and junB was studied after 15 min of normothermic and hypothermic (33 degrees C) transient forebrain ischaemia in the rat, induced by common carotid occlusion combined with systemic hypotension [4].
• In contrast, administration of the progesterone receptor antagonist RU486 (10 mg/kg s.c.) on Day 19 induced preterm labor and a premature increase in mRNA levels of c-fos, fra-1, fra-2, and junB [5].

High impact information on Fosl1

• Neoplastic transformation of rat thyroid cells requires the junB and fra-1 gene induction which is dependent on the HMGI-C gene product [6].
• The strongest effect is represented by the dramatic junB and fra-1 gene induction, which is prevented in cell lines expressing the antisense HMGI-C [6].
• A C-terminal domain in FosB, absent in FosB/SF and Fra-1, which is able to interact with the TATA binding protein, is required for altered cell growth [7].
• We have also demonstrated that an activator protein-1 transcription factor, the 35-kDa fos-related antigen, can be induced and elevated for at least 1 year after kainate treatment [8].
• Accumulation of Fra-1 in ras-transformed cells depends on both transcriptional autoregulation and MEK-dependent posttranslational stabilization [9].

Chemical compound and disease context of Fosl1

• Hexamethylene bisacetamide (HMBA)-induced growth inhibition and differentiation of the rat C6 glioma cell line were found to be accompanied by down-regulation of the constitutively expressed fra-1 gene [2].

Biological context of Fosl1

• Gene expression for Fos was suppressed at both times, while that for Fosl1 and Jun was augmented at 12 h and suppressed at 48 h [10].
• fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen [11].
• The posttranslational stabilization results in a drastic increase in the Fra-1 half-life in ras-transformed cells and is totally dependent on the activity of the MEK/ERK phosphorylation pathway [9].
• The analysis of the Fra-1 transactivation potential shows that the protein is able to stimulate a heterologous promoter in a ras-dependent manner, but the transactivating activity requires the recruitment of a heterodimeric partner [9].
• Together, these data identify fra-1 as a unique member of the fos gene family which is under positive control by AP-1 activity [12].

Anatomical context of Fosl1

• Constitutive expression of c-Fos, FosB, Fra-1, or c-Jun in rat fibroblasts leads to up-regulation of the immediate-early gene fra-1 [12].
• It was previously shown that the fra-1 gene product is upregulated by various oncogenes and is involved in the in vitro and in vivo transformation of thyroid cells [9].
• Learning-dependent activation of Fra-1: involvement of ventral hippocampus and SNc/VTA complex in learning and habit formation [13].
• Statistical analysis of the data revealed over-expression of Fra-1, Fra-2, JunB and JunD proteins in all stages of differentiation of chondrocytes derived from the mandibular condylar cartilage of animals fed on a hard diet [14].
• In both cell types, c-Fos and Fra-1 proteins increased after EGF treatment, but differences in the induction of Jun proteins were noted, with an increase of c-Jun in hepatocytes and an increase of JunB in 7777 cells [15].

Associations of Fosl1 with chemical compounds

• Contrary to the expectations, fra-1 overexpression was found to inhibit proliferation and induce morphological differentiation of C6 cells [2].
• Furthermore, all three differentiation inducers studied viz. dibutyryl cyclic AMP (dbcAMP), staurosporine, and HMBA have greater growth inhibitory effect on fra-1 overexpressing clones as compared to the parental C6 cells. dbcAMP and staurosporine not only inhibit proliferation but bring about complete apoptosis of fra-1 overexpressing clones [2].
• Absence of a persistently elevated 37 kDa fos-related antigen and AP-1-like DNA-binding activity in the brains of kainic acid-treated fosB null mice [16].
• Nodularin up-regulated induction of c-jun, jun-B,jun-D,c-fos,fos-B, and fra-1 mRNA transcripts in rat liver after i.p. administration, and the accumulation of the mRNA transcripts was sustained for over 9 h after treatment [17].
• H(2)O(2)-induced egr-1, fra-1, and c-jun gene expression is mediated by tyrosine kinase in aortic smooth muscle cells [18].

Physical interactions of Fosl1

• Using electrophoretic mobility-shift assay and one-dimensional Western blot, we here report that delta9-THC increases Activator protein-1 (AP-1) DNA-binding and Fos-related antigen activity in discrete areas of the rat brain [19].

Other interactions of Fosl1

• The condylar cartilage of both groups was immunostained using specific antibodies against Fra-1, Fra-2, JunB and JunD [14].
• Single IMO elicited rapid induction of c-Fos and phosphorylation of cyclic AMP response element-binding protein (CREB) without changing the expression of early growth response (Egr)1, Fos-related antigen (Fra)-2 or phosphorylated activating transcription factor-2 [20].
• Addition of bFGF to SMC activates the extracellular signal-regulated kinases 1/2 (ERK1/2) resulting in their translocation into the nucleus and subsequent induction of Fra-1 [21].
• Activator protein-1 (AP-1) binding to DNA increased more in VSMC from old versus young rats (P < 0.02) and was related to increased expression of its components, c-Fos, Fra-1, and JunD [22].
• Whereas AT(1) and AT(2) receptors involve the Fos-related antigen Fra-2, AT(1) receptor transcriptional effects include pCREB and ERK2, indicating common as well as different regulatory mechanisms for each receptor type [23].

Analytical, diagnostic and therapeutic context of Fosl1

• Using RNA interference technology, fra-1 gene silenced RPM cells were assayed by real-time quantitative PCR for the expression of possible fra-1-regulated genes [1].
• Microarray analysis and RNA silencing link fra-1 to cd44 and c-met expression in mesothelioma [1].
• After oligonucleotide microarray analysis (Affymetrix array) of normal rat pleural mesothelial (RPM) cells, RPM cells exposed to crocidolite asbestos, and rat mesotheliomas, subsets of genes that changed in expression were categorized, including the highly up-regulated, early response proto-oncogene, fra-1 [1].
• Immediate-early gene expression was examined by Northern blotting: both thrombin and PDGF induced egr-1, c-fos, c-jun, junB, and fra-1 mRNAs within 15 min; the response was maximal at 30-60 min (increases ranging from 2.9- to 9.3-fold over control serum-deprived cells) and returned to base-line levels within 2-4 h [24].
• Immunocytochemistry and western blot analysis using an antibody that cross-reacts with all known FRAs showed that a 35-kDa FRA was induced at high levels in both the hippocampus and striatum for up to 1 month by KA [25].

References