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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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No annotation is available in this section for this article. The content below is taken from a related TF, FOSL1 (Homo sapiens).

FOSL1 (FRA1) is a basic leucine zipper (bZIP) transcription factor. FOSL1 dimerizes with members of the JUN family (JUN, JUNB, JUND) and, through a 12-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE, TGAC/GTCA), regulates gene expression involved in physiologic and pathologic processes.[1] In addition to the JUN proteins, FOSL1 can interact with ATF4 (activating transcription factor 4) and USF1 (upstream stimulating factor 1). Thus, by dimerizing with proteins of the JUN family, and with other transcription factors, FOSL1 can distinctly regulate both cell type- and stimulus-specific gene expression involved in various physiologic and pathologic processes, in a TRE-dependent and -independent manner.[2][3] FOSL1 is covalently modified by posttranslational modifications via phosphorylation at serine and threonine residues, mainly through Rsk and ERK1/2/5 MAP kinases. [4][5][6][7] These modifications are known to affect both the protein stability and the transactivation potential of FOSL1[8]. FOSL1 contains a nuclear localization signal and is mostly localized in the nucleus. However, immunolocalization studies revealed the presence of FOSL1 in the cytoplasm in certain situations, such as in the presence of elevated levels of oxidative stress[9] and in cancerous tissues[10]. Also, it appears that this trafficking affects the gene expression as well as the stability of this transcription factor.[9]

Conventional genetic deletion of the FOSL1 in mice results in embryonic lethality, because this transcription factor is critical for extra-embryonic tissue development.[11] However, mice lacking FOSL1, specifically in the embryo, develop normally without an overt phenotype and these mice subsequently display reduced bone mass formation and osteopenia. [12] Ectopic expression of FOSL1 under the control of a ubiquitous promoter induces increased bone formation and osteosclerosis in mice.[13] Genetic complementation studies have demonstrated an overlapping function between FOSL1 and FOS in bone growth in mice. No genetic mutations leading to activation or inactivation of this transcription factor in human disease development and in malignancies have been yet documented. Increased levels of FOSL1 mRNA transcripts, however, have been detected in various tumor tissues/cell types. [14] Data generated in several labs have unequivocally demonstrated a causative role for FOSL1 in cancer cell progression and invasion. Overexpression of FOSL1 induces fibroblastoid phenotype with an increased malignant potential in several cancer cell types, while silencing or knockdown of the FOSL1 expression reverses this malignant phenotype.[3][14]

The expression of FOSL1 is very low in various adult tissues, but its transcription is strongly inducible by mitogens and inflammatory cytokines as well by various environmental toxicants, carcinogens and pathogens, mainly through EGFR-activated Ras signaling. [15][16][17] This pathway is known to promote tumor development and progression in vivo and is frequently mutated in various human lung tumors. Data from several studies performed in cell cultures illuminates a potential role for FOSL1 both in physiologic and pathophysiologic processes.[2] However, further studies using "floxed" mice are warranted to dissect the exact role(s) of this proto-oncogene in the development and progression of various diseases, including malignancy.

  1. Cohen DR and Curran T. fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen. Mol. Cell. Biol., 8(5):2063-9. (PMID 3133553)
  2. Reddy SP and Mossman BT. Role and regulation of activator protein-1 in toxicant-induced responses of the lung. Am. J. Physiol. Lung Cell Mol. Physiol., 283(6):L1161-78. (PMID 12424143)
  3. Verde P et al. Deciphering AP-1 function in tumorigenesis: fra-ternizing on target promoters. Cell Cycle, 6(21):2633-9. (PMID 17957143)
  4. Gruda MC et al. Regulation of Fra-1 and Fra-2 phosphorylation differs during the cell cycle of fibroblasts and phosphorylation in vitro by MAP kinase affects DNA binding activity. Oncogene, 9(9):2537-47. (PMID 8058317)
  5. Casalino L et al. Accumulation of Fra-1 in ras-transformed cells depends on both transcriptional autoregulation and MEK-dependent posttranslational stabilization. Mol. Cell. Biol., 23(12):4401-15. (PMID 12773579)
  6. Vial E and Marshall CJ. Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells. J. Cell. Sci., 116(Pt 24):4957-63. (PMID 14625389)
  7. Murphy LO et al. A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol. Cell. Biol., 24(1):144-53. (PMID 14673150)
  8. Gomard T et al. Fos family protein degradation by the proteasome. Biochem. Soc. Trans., 36(Pt 5):858-63. (PMID 18793151)
  9. Burch PM et al. An 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. Mol. Cell. Biol., 24(11):4696-709. (PMID 15143165)
  1. Song Y et al. An association of a simultaneous nuclear and cytoplasmic localization of Fra-1 with breast malignancy. BMC Cancer, 6:298. (PMID 17192200)
  2. Schreiber M et al. Placental vascularisation requires the AP-1 component fra1. Development, 127(22):4937-48. (PMID 11044407)
  3. Eferl R et al. The Fos-related antigen Fra-1 is an activator of bone matrix formation. EMBO J., 23(14):2789-99. (PMID 15229648)
  4. Jochum W et al. Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat. Med., 6(9):980-4. (PMID 10973316)
  5. Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis. Eur. J. Cancer, 41(16):2449-61. (PMID 16199154)
  6. Zhang Q et al. Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. Am. J. Respir. Cell Mol. Biol., 32(1):72-81. (PMID 15528491)
  7. Zhang Q et al. A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression. J. Biol. Chem., 281(15):10174-81. (PMID 16490785)
  8. Young MR and Colburn NH. Fra-1 a target for cancer prevention or intervention. Gene, 379:1-11. (PMID 16784822)
No annotation is available in this section for this article. The content below is taken from a related TF, FOSL1 (Homo sapiens).
FIGURE 1 Regulation of gene expression by FOSL1 based JUN/AP1 complex
FOSL1 is a dimeric partner of AP1 transcription factor. After heteodimerization with the JUN family members, JUN, JUNB or JUND, FOSL1 (F1) binds to the TPA response element (TRE) and differentially regulates gene expression implicated in both normal and pathologic processes.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.