* 164810
FOS PROTOONCOGENE, AP1 TRANSCRIPTION FACTOR SUBUNIT; FOS
Alternative titles; symbols
V-FOS FBJ MURINE OSTEOSARCOMA VIRAL ONCOGENE HOMOLOG
ONCOGENE FOS
FBJ OSTEOSARCOMA VIRUS
HGNC Approved Gene Symbol: FOS
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:75,278,828-75,282,230 (from NCBI)
TEXT
Description
The human oncogene c-fos is homologous to the Finkel-Biskis-Jinkins (FBJ) murine osteosarcoma virus oncogene. FOS was the first transcription factor identified that has a critical function in regulating the development of cells destined to form and maintain the skeleton. FOS is also a major component of the activator protein-1 (AP-1) transcription factor complex, which includes members of the JUN family (see also 165160).
Cloning and Expression
Van Straaten et al. (1983) determined that the human FOS gene encodes a predicted 380-amino acid protein. Northern blot analysis revealed that FOS is expressed as a 2.2-kb mRNA in placenta and fetal membranes.
Gene Structure
Van Straaten et al. (1983) reported that the human FOS gene contains 3 introns and spans approximately 4 kb.
Gene Function
Muller et al. (1983) reported that the level of the c-fos gene transcripts is 100-fold greater in human term fetal membranes than in other normal human tissues and cells. These levels of c-fos expression in human amniotic and chorionic cells are close to that of v-fos expression that results in the induction of osteosarcomas in mice and transformation of fibroblasts in vitro. The human c-fms gene (164770) is expressed at high levels in term placenta and trophoblastic cells. Muller et al. (1983) suggested that the physiologic role of the proteins encoded by the FOS and FMS genes may be related to these embryo-derived cells whose primary functions are protection and nourishment of the human fetus. Using the technique of in situ hybridization, Dony and Gruss (1987) demonstrated that stage-specific expression of the FOS gene in mouse embryos is restricted to the perichondrial growth regions of the cartilaginous skeleton. The possibility of a defect in FOS in a skeletal dysplasia is raised by these findings.
Visvader et al. (1988) described 2 elements in the FOS promoter that can mediate the induction of FOS by nerve growth factor (162030).
In studies of the Hayflick phenomenon (Hayflick, 1965), i.e., the finite life span of cultured nonneoplastic cells, Seshadri and Campisi (1990) demonstrated loss of FOS inducibility as the result of a specific, transcriptional block. They interpreted the multiple changes in gene expression as supporting the view that cellular senescence is a process of terminal differentiation.
The FOS and JUN oncoproteins form dimeric complexes that stimulate transcription of genes containing AP-1 regulatory elements. Bakin and Curran (1999) found, by representational difference analysis, that expression of DNA 5-methylcytosine transferase (DNMT1; 126375) in FOS-transformed cells is 3 times the expression in normal fibroblasts and that FOS-transformed cells contain about 20% more 5-methylcytosine than normal fibroblasts. Transfection of the DNMT1 gene induced morphologic transformation, whereas inhibition of DNMT1 expression or activity resulted in reversion of FOS transformation. Inhibition of histone deacetylase (601241), which associates with methylated DNA, also caused reversion. These results suggest that FOS may transform cells through alterations in DNA methylation and in histone deacetylation.
Grigoriadis et al. (1995) reviewed the role of FOS in bone development and the relationship to SCF1 (120420) and SRC (190090) which have a role in osteoclast development.
The POMC gene (176830) is occasionally expressed in nonpituitary tumors leading to Cushing syndrome (219080). Bronchial carcinoid tumors, one of the most frequent sources for ectopic ACTH secretion, often display numerous features of the corticotroph phenotype. To identify new markers of corticotroph differentiation in these tumors, Le Tallec et al. (2002) compared the pattern of POMC expression in ACTH-secreting (ACTH+) and nonsecreting (ACTH-) bronchial carcinoids by differential display/RT-PCR. In ACTH+ tumors, beside the expected POMC gene, they identified cFos and KIAA1775, a large expressed sequence tag encoding a putative protocadherin-related protein. On the other hand, the tetraspanin TM4SF5 gene (604657) was specifically expressed in ACTH- tumors. The authors concluded that corticotroph differentiation of bronchial carcinoid tumors is accompanied by induction and repression of specific genes.
Hikasa et al. (2003) found p21 (CDKN1A; 116899) downregulation in conjunction with c-fos upregulation in the lymphocytes of patients with rheumatoid arthritis. Phosphorylation of STAT1 (600555) was also decreased in rheumatoid arthritis lymphocytes. Hikasa et al. (2003) determined that c-fos overexpression led to downregulated phosphorylation and dimerization of STAT1, which in turn downregulated p21 gene expression. They concluded that this regulatory pathway may enhance the proliferation of lymphocytes in rheumatoid arthritis patients.
Biochemical Features
Glover and Harrison (1995) stated that members of the FOS and JUN families of eukaryotic transcription factors heterodimerize to form DNA-binding complexes. Each protein contains a bZIP region consisting of a basic DNA-binding domain and a leucine zipper domain. The authors determined the crystal structure of a heterodimer of the bZIP domains of FOS and JUN bound to DNA.
Mapping
By study of mouse-human cell hybrids and by in situ hybridization, Barker et al. (1984) assigned the FOS gene to 14q21-q31. Ekstrand and Zech (1987) mapped the FOS gene to 14q24.3-q31. They pointed to the high number of neoplasms that have been found to have aberrations in this chromosome region.
Molecular Genetics
The long bones of transgenic mice overexpressing the FOS protooncogene show lesions of fibrous dysplasia characterized by intense marrow fibrosis and increased rates of bone turnover (Ruther et al., 1987). In all 8 patients with fibrous dysplasia studied by Candeliere et al. (1995), high levels of FOS expression were detected in the bone lesions. No expression of FOS was detected in bone specimens from normal subjects or from specimens of normal bone obtained from patients with fibrous dysplasia. The cells that expressed FOS in the dysplastic lesions were fibroblastic and populated the marrow space. A very low level of FOS expression was detected in the biopsy specimens from the patients with other bone diseases. One patient with polyostotic fibrous dysplasia had the arg201-to-cys mutation (139320.0008) and 1 patient with the McCune-Albright syndrome (174800) had the arg201-to-his mutation (139320.0009) in the GNAS1 gene. The increased expression of the FOS oncogene, presumably a consequence of increased adenylate cyclase activity, may be important in the pathogenesis of the bone lesions in patients with fibrous dysplasia.
Rogaev et al. (1993) excluded the FOS open reading frame as the site of the type 3, or chromosome 14-linked, form of familial Alzheimer disease (607822).
Animal Model
Stable expression of c-fos in mice has been demonstrated in developing bones and teeth, hematopoietic cells, germ cells, and the central nervous system. The gene product is thought to have an important role in signal transduction, cell proliferation, and differentiation. Wang et al. (1991) demonstrated that overexpression of the gene in transgenic and chimeric mice specifically affects bone, cartilage, and hematopoietic cell development. Wang et al. (1992) studied the effects of lack of c-fos by gene targeting in embryonic stem cells. They reported that mice heterozygous for lack of the gene appeared normal, although females exhibited a distorted transmission frequency. All homozygous fos -/- mice were growth-retarded, developed osteopetrosis with deficiencies in bone remodeling and tooth eruption, and had altered hematopoiesis. Johnson et al. (1992) found similar results. Homozygous mutants showed reduced placental and fetal weights and significant loss of viability at birth. However, approximately 40% of the homozygous mutants survived and grew at normal rates until severe osteopetrosis, characterized by foreshortening of the long bones, ossification of the marrow space, and absence of tooth eruption, began to develop at approximately 11 days. Among other abnormalities, these mice showed delayed or absent gametogenesis, lymphopenia, and altered behavior. Despite these defects, many lived as long as their wildtype or heterozygous littermates (currently 7 months).
Grigoriadis et al. (1994) found that FOS mutant mice that develop osteopetrosis have a block in the differentiation of bone-resorbing osteoclasts that was intrinsic to hematopoietic cells. Bone marrow transplantation rescued the osteopetrosis, and ectopic FOS expression overcame the differentiation block. The lack of FOS also caused a lineage shift between osteoclasts and macrophages that resulted in increased numbers of bone marrow macrophages. These results indicated that FOS is a key regulator of osteoclast-macrophage lineage determination in vivo.
Using the multistep skin carcinogenesis model, Saez et al. (1995) tested the ability of c-fos-deficient mice to develop cancer. Upon treatment with a tumor promoter, c-fos knockout mice carrying a v-H-ras transgene were able to develop benign tumors with similar kinetics and relative incidence as wildtype animals. However, c-fos-deficient papillomas quickly became very dry and hyperkeratotic, taking on an elongated, horny appearance. While wildtype papillomas eventually progressed into malignant tumors, c-fos-deficient tumors failed to undergo malignant conversion. Experiments in which v-H-ras-expressing keratinocytes were grafted onto nude mice suggested that c-fos-deficient cells have an intrinsic defect that hinders tumorigenesis. The results of Saez et al. (1995) suggested that a member of the AP-1 family of transcription factors is required for the development of a malignant tumor.
Excitotoxicity is a process in which glutamate or other excitatory amino acids induce neuronal cell death. Excitotoxicity may contribute to human neuronal cell death caused by acute insults and chronic degeneration in the central nervous system. Evidence suggests that FOS is essential in regulating neuronal cell survival versus death. Although FOS is induced by neuronal activity, whether and how FOS is involved in excitotoxicity was unknown. To address this issue, Zhang et al. (2002) generated a mouse in which FOS expression was largely eliminated in the hippocampus. They found that these mutant mice had more severe kainic acid-induced seizures, increased neuronal excitability, and neuronal cell death, compared with control mice. Moreover, FOS regulates the expression of the kainic acid receptor GLUR6 (138244) and brain-derived neurotrophic factor (BDNF; 113505), both in vivo and in vitro. The results suggested that FOS is a genetic regulator for cellular mechanisms mediating neuronal excitability and survival.
Using a Drosophila model synapse, Sanyal et al. (2002) analyzed cellular functions and regulation of the immediate-early transcription factor AP-1, a heterodimer of the basic leucine zipper proteins FOS and JUN (165160). They observed that AP-1 positively regulates synaptic strength and synapse number, thus showing a greater range of influence than CREB (123810). Observations from genetic epistasis and RNA quantification experiments indicate that AP-1 acts upstream of CREB, regulates levels of CREB mRNA, and functions at the top of the hierarchy of transcription factors known to regulate long-term plasticity. A JUN-kinase signaling module provided a CREB-independent route for neuronal AP-1 activation; thus, CREB regulation of AP-1 expression may, in some neurons, constitute a positive feedback loop rather than the primary step in AP-1 activation.
David et al. (2005) demonstrated that ribosomal protein S6 kinase-2 (RSK2; 300075)-null mice develop progressive osteopenia due to impaired osteoblast function and normal osteoclast differentiation. They also observed that c-fos-dependent osteosarcoma formation was impaired in the absence of Rsk2; the lack of c-fos phosphorylation led to reduced c-fos protein levels, which were thought to be responsible for the observed decreased proliferation and increased apoptosis of transformed osteoblasts. David et al. (2005) concluded that Rsk2-dependent stabilization of c-fos is essential for osteosarcoma formation in mice.
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