Alternative titles; symbols
HGNC Approved Gene Symbol: FOSL1
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:65,892,049-65,900,545 (from NCBI)
Activator protein-1 (AP-1) is a dimeric transcription factor formed by FOS proteins, including FOSL1, and JUN proteins (e.g., 165160), both of which are required for bone formation and remodeling. FOSL1 is an activator of bone matrix formation (summary by Eferl et al., 2004).
Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Mice lacking Fos (164810) develop osteopetrosis (see 166600) due to an early differentiation block in the osteoclast lineage. Matsuo et al. (2000) investigated the mechanism by which Fos exerts its specific function in osteoclast differentiation. They showed by retroviral-gene transfer that all 4 Fos proteins--Fos, FosB (164772), Fosl1, and Fosl2 (601575)--but not the Jun proteins (e.g., 165160), rescued the differentiation block in vitro. Structure-function analysis demonstrated that the major carboxy-terminal transactivation domains of Fos and FosB are dispensable and that Fosl1, which lacks transactivation domains, has the highest rescue activity. Moreover, a transgene expressing Fosl1 rescued the osteopetrosis of Fos mutant mice in vivo. The osteoclast differentiation factor Rankl (602642) induced transcription of Fosl1 in a Fos-dependent manner, thereby establishing a link between Rank signaling and the expression of Ap1 proteins in osteoclast differentiation.
Kustikova et al. (1998) found a correlation between Fra1 expression and mesenchymal characteristics in cell lines of epithelial tumor origin. Exogenous expression of Fra1 in epithelioid cells resulted in morphologic changes that resembled fibroblastoid conversion, with cells acquiring elongated shape and increased motility and invasiveness in vitro. The morphologic alterations were accompanied by transcriptional activation of genes whose expression is often induced at late stages of tumor progression.
Sinke et al. (1993) applied the designation 'reverse mapping' to the identification of a previously known gene within a cosmid for which the localization was already known. For the identification of sequence tagged sites (STSs) within cosmid clones derived from the 11q13 region, they subcloned a number of single-copy BamHI fragments. In one of the subclones, they found a sequence that matched perfectly with the 5-prime end of the cDNA sequence for human FRA1. The FRA1 fragment was contained within a clone previously mapped to region V of a long-range contig map of 11q13. The localization to chromosome 11 was cross-checked by hybridization to a panel of somatic cell hybrids. Thus another oncogene was assigned to the region implicated in a number of different forms of malignancy.
Eferl et al. (2004) noted that Fra1 knockout in mice results in embryonic death in utero, likely due to placental defects. Using conditional deletion, they deleted Fra1 throughout mouse embryos, but not in extraembryonic tissues, such as placenta. Homozygous mutant mice were viable, but they developed osteopenia due to reduced bone formation. The numbers of osteoblasts and osteoclasts were unchanged, although in vitro and in vivo analysis revealed severely reduced bone-forming activity of osteoblasts. Eferl et al. (2004) concluded that the defect was likely due to reduced expression of the bone matrix genes osteocalcin (112260), collagen-1A2 (120160), and matrix Gla protein (154870).
Eferl, R., Hoebertz, A., Schilling, A. F., Rath, M., Karreth, F., Kenner, L., Amling, M., Wagner, E. F. The Fos-related antigen Fra-1 is an activator of bone matrix formation. EMBO J. 23: 2789-2799, 2004. [PubMed: 15229648] [Full Text: https://doi.org/10.1038/sj.emboj.7600282]
Kustikova, O., Kramerov, D., Grigorian, M., Berezin, V., Bock, E., Lukanidin, E., Tulchinsky, E. Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Molec. Cell. Biol. 18: 7095-7105, 1998. [PubMed: 9819396] [Full Text: https://doi.org/10.1128/MCB.18.12.7095]
Matsuo, K., Owens, J. M., Tonko, M., Elliott, C., Chambers, T. J., Wagner, E. F. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nature Genet. 24: 184-187, 2000. [PubMed: 10655067] [Full Text: https://doi.org/10.1038/72855]
Sinke, R. J., Tanigami, A., Nakamura, Y., Geurts van Kessel, A. Reverse mapping of the gene encoding the human fos-related antigen-1 (fra-1) within chromosome band 11q13. Genomics 18: 165 only, 1993. [PubMed: 8276409] [Full Text: https://doi.org/10.1006/geno.1993.1447]