FLI1

Friend leukemia virus integration 1
PDB rendering based on 1fli.
Available structures PDB 1FLI, 1X66, 2YTU
Identifiers
Symbols	FLI1; EWSR2; SIC-1
External IDs	OMIM: 193067 MGI: 95554 HomoloGene: 55624 GeneCards: FLI1 Gene
Gene Ontology Molecular function • DNA binding • sequence-specific DNA binding transcription factor activity • sequence-specific DNA binding Cellular component • nucleus Biological process • regulation of transcription, DNA-dependent • hemostasis • organ morphogenesis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2313	14247
Ensembl	ENSG00000151702	ENSMUSG00000016087
UniProt	Q01543	P26323
RefSeq (mRNA)	NM_001167681.2	NM_008026.4
RefSeq (protein)	NP_001161153.1	NP_032052.1
Location (UCSC)	Chr 11: 128.56 – 128.68 Mb	Chr 9: 32.23 – 32.35 Mb
PubMed search	[1]	[2]

Friend leukemia integration 1 transcription factor (FLI1), also known as proto-oncogene Fli-1 or transcription factor ERGB, is a protein that in humans is encoded by the human FLI1 gene.

Function

Fli-1 is a member of the ETS transcription factor family that was first identified in erythroleukemias induced by Friend Murine Leukemia Virus (F-MuLV). Fli-1 is activated through retroviral insertional mutagenesis in 90% of F-MuLV-induced erythroleukemias. The constitutive activation of fli-1 in erythroblasts leads to a dramatic shift in the Epo/Epo-R signal transduction pathway, blocking erythroid differentiation, activating the Ras pathway, and resulting in massive Epo-independent proliferation of erythroblasts. These results suggest that Fli-1 overexpression in erythroblasts alters their responsiveness to Epo and triggers abnormal proliferation by switching the signaling event(s) associated with terminal differentiation to proliferation.

Clinical significance

In addition to Friend erythroleukemia, proviral integration at the fli-1 locus also occurs in leukemias induced by the 10A1, Graffi, and Cas-Br-E viruses. Fli-1 aberrant expression is also associated with chromosomal abnormalities in humans. In pediatric Ewing’s sarcoma a chromosomal translocation generates a fusion of the 5’ transactivation domain of EWS with the 3’ Ets domain of Fli-1. The resulting fusion oncoprotein, EWS/Fli-1, acts as an aberrant transcriptional activator. with strong transforming capabilities. The importance of Fli-1 in the development of human leukemia, such as acute myelogenous leukemia (AML), has been demonstrated in studies of translocation involving the Tel transcription factor, which interacts with Fli-1 through protein-protein interactions. A recent study has demonstrated high levels of Fli-1 expression in several benign and malignant neoplasms using immunohistochemistry.^{[citation needed]}

A possible association with Paris-Trousseau syndrome has been suggested.

Further reading

• Ben-David Y, Giddens EB, Bernstein A (February 1990). "Identification and mapping of a common proviral integration site Fli-1 in erythroleukemia cells induced by Friend murine leukemia virus". Proc. Natl. Acad. Sci. U.S.A. 87 (4): 1332–6. doi:10.1073/pnas.87.4.1332. PMC 53469. PMID 2304901. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=53469. 
• Ben-David Y, Giddens EB, Letwin K, Bernstein A (June 1991). "Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1". Genes Dev. 5 (6): 908–18. doi:10.1101/gad.5.6.908. PMID 2044959. 
• Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G (September 1992). "Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours". Nature 359 (6391): 162–5. doi:10.1038/359162a0. PMID 1522903. 
• Pereira R, Quang CT, Lesault I, Dolznig H, Beug H, Ghysdael J (February 1999). "FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts". Oncogene 18 (8): 1597–608. doi:10.1038/sj.onc.1202534. PMID 10102630. 
• Tamir A, Howard J, Higgins RR, Li YJ, Berger L, Zacksenhaus E, Reis M, Ben-David Y (June 1999). "Fli-1, an Ets-related transcription factor, regulates erythropoietin-induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation". Mol. Cell. Biol. 19 (6): 4452–64. PMC 104404. PMID 10330185. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=104404. 
• Zochodne B, Truong AH, Stetler K, Higgins RR, Howard J, Dumont D, Berger SA, Ben-David Y (May 2000). "Epo regulates erythroid proliferation and differentiation through distinct signaling pathways: implication for erythropoiesis and Friend virus-induced erythroleukemia". Oncogene 19 (19): 2296–304. doi:10.1038/sj.onc.1203590. PMID 10822380. 
• Starck J, Doubeikovski A, Sarrazin S, Gonnet C, Rao G, Skoultchi A, Godet J, Dusanter-Fourt I, Morle F (January 1999). "Spi-1/PU.1 is a positive regulator of the Fli-1 gene involved in inhibition of erythroid differentiation in friend erythroleukemic cell lines". Mol. Cell. Biol. 19 (1): 121–35. PMC 83871. PMID 9858537. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=83871. 
• Truong AH, Ben-David Y (December 2000). "The role of Fli-1 in normal cell function and malignant transformation". Oncogene 19 (55): 6482–9. doi:10.1038/sj.onc.1204042. PMID 11175364. 
• Ohno T, Rao VN, Reddy ES (December 1993). "EWS/Fli-1 chimeric protein is a transcriptional activator". Cancer Res. 53 (24): 5859–63. PMID 7503813. 
• Dhulipala PD, Lee L, Rao VN, Reddy ES (September 1998). "Fli-1b is generated by usage of differential splicing and alternative promoter". Oncogene 17 (9): 1149–57. doi:10.1038/sj.onc.1202030. PMID 9764825. 
• Rao VN, Ohno T, Prasad DD, Bhattacharya G, Reddy ES (August 1993). "Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein". Oncogene 8 (8): 2167–73. PMID 8336942. 
• Ban J, Siligan C, Kreppel M et al (2007). "EWS-FLI1 in Ewing's sarcoma: real targets and collateral damage". Adv. Exp. Med. Biol. 587: 41–52. PMID 17163154. 
• Prasad DD, Rao VN, Reddy ES (1992). "Structure and expression of human Fli-1 gene". Cancer Res. 52 (20): 5833–7. PMID 1394211. 
• Watson DK, Smyth FE, Thompson DM et al (1992). "The ERGB/Fli-1 gene: isolation and characterization of a new member of the family of human ETS transcription factors". Cell Growth Differ. 3 (10): 705–13. PMID 1445800. 
• Delattre O, Zucman J, Plougastel B et al (1992). "Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours". Nature 359 (6391): 162–5. doi:10.1038/359162a0. PMID 1522903. 
• Baud V, Lipinski M, Rassart E et al (1992). "The human homolog of the mouse common viral integration region, FLI1, maps to 11q23-q24". Genomics 11 (1): 223–4. doi:10.1016/0888-7543(91)90124-W. PMID 1765382. 
• Bergeron D, Poliquin L, Kozak CA, Rassart E (1991). "Identification of a common viral integration region in Cas-Br-E murine leukemia virus-induced non-T-, non-B-cell lymphomas". J. Virol. 65 (1): 7–15. PMC 240483. PMID 1845910. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=240483. 
• Bhagirath T, Abe S, Nojima T, Yoshida MC (1995). "Molecular analysis of a t(11;22) translocation junction in a case of Ewing's sarcoma". Genes Chromosomes Cancer 13 (2): 126–32. doi:10.1002/gcc.2870130209. PMID 7542907. 
• Liang H, Mao X, Olejniczak ET et al (1995). "Solution structure of the ets domain of Fli-1 when bound to DNA". Nat. Struct. Biol. 1 (12): 871–5. doi:10.1038/nsb1294-871. PMID 7773776. 
• May WA, Lessnick SL, Braun BS et al (1994). "The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1". Mol. Cell. Biol. 13 (12): 7393–8. PMC 364810. PMID 8246959. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=364810. 
• Hromas R, May W, Denny C et al (1993). "Human FLI-1 localizes to chromosome 11Q24 and has an aberrant transcript in neuroepithelioma". Biochim. Biophys. Acta 1172 (1–2): 155–8. PMID 8439553. 
• Magnaghi-Jaulin L, Masutani H, Robin P et al (1996). "SRE elements are binding sites for the fusion protein EWS-FLI-1". Nucleic Acids Res. 24 (6): 1052–8. doi:10.1093/nar/24.6.1052. PMC 145748. PMID 8604338. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=145748. 
• Barbeau B, Bergeron D, Beaulieu M et al (1996). "Characterization of the human and mouse Fli-1 promoter regions". Biochim. Biophys. Acta 1307 (2): 220–32. PMID 8679708. 
• Watson DK, Robinson L, Hodge DR et al (1997). "FLI1 and EWS-FLI1 function as ternary complex factors and ELK1 and SAP1a function as ternary and quaternary complex factors on the Egr1 promoter serum response elements". Oncogene 14 (2): 213–21. doi:10.1038/sj.onc.1200839. PMID 9010223. 
• Kwiatkowski BA, Bastian LS, Bauer TR et al (1998). "The ets family member Tel binds to the Fli-1 oncoprotein and inhibits its transcriptional activity". J. Biol. Chem. 273 (28): 17525–30. doi:10.1074/jbc.273.28.17525. PMID 9651344. 
• Carrère S, Verger A, Flourens A et al (1998). "Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains". Oncogene 16 (25): 3261–8. doi:10.1038/sj.onc.1201868. PMID 9681824. 
• Zucman-Rossi J, Legoix P, Victor JM et al (1998). "Chromosome translocation based on illegitimate recombination in human tumors". Proc. Natl. Acad. Sci. U.S.A. 95 (20): 11786–91. doi:10.1073/pnas.95.20.11786. PMC 21718. PMID 9751743. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=21718. 
• Dalgleish P, Sharrocks AD (2000). "The mechanism of complex formation between Fli-1 and SRF transcription factors". Nucleic Acids Res. 28 (2): 560–9. doi:10.1093/nar/28.2.560. PMC 102515. PMID 10606656. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=102515. 
• Knoop LL, Baker SJ (2000). "The splicing factor U1C represses EWS/FLI-mediated transactivation". J. Biol. Chem. 275 (32): 24865–71. doi:10.1074/jbc.M001661200. PMID 10827180. 
• Spyropoulos DD, Pharr PN, Lavenburg KR et al (2000). "Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor". Mol. Cell. Biol. 20 (15): 5643–52. doi:10.1128/MCB.20.15.5643-5652.2000. PMC 86032. PMID 10891501. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=86032. 
• Mastrangelo T, Modena P, Tornielli S et al (2000). "A novel zinc finger gene is fused to EWS in small round cell tumor". Oncogene 19 (33): 3799–804. doi:10.1038/sj.onc.1203762. PMID 10949935. 

External links

• MeSH FLI1+protein,+human

This article incorporates text from the United States National Library of Medicine, which is in the public domain.