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 retroviralinsertional 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.
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 EWSR1 (also known as 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.
^Baud V, Lipinski M, Rassart E, Poliquin L, Bergeron D (September 1991). "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. PMID1765382.
^Prasad DD, Rao VN, Reddy ES (October 1992). "Structure and expression of human Fli-1 gene". Cancer Research. 52 (20): 5833–7. PMID1394211.
^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. PMID8336942.
^Ohno T, Rao VN, Reddy ES (December 1993). "EWS/Fli-1 chimeric protein is a transcriptional activator". Cancer Res. 53 (24): 5859–63. PMID7503813.
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. PMID2044959.
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. PMID1522903.
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. PMID10102630.
Ohno T, Rao VN, Reddy ES (December 1993). "EWS/Fli-1 chimeric protein is a transcriptional activator". Cancer Res. 53 (24): 5859–63. PMID7503813.
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. PMID9764825.
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. PMID8336942.
Prasad DD, Rao VN, Reddy ES (1992). "Structure and expression of human Fli-1 gene". Cancer Res. 52 (20): 5833–7. PMID1394211.
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. PMID1445800.
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. PMID1522903.
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. PMID7542907.
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. PMID7773776.
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. doi:10.1016/0167-4781(93)90283-J. PMID8439553.
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. PMID9010223.
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. PMID9651344.
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. PMID9681824.