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Gene Review

FLI1  -  Fli-1 proto-oncogene, ETS transcription...

Homo sapiens

Synonyms: EWSR2, Friend leukemia integration 1 transcription factor, Proto-oncogene Fli-1, SIC-1, Transcription factor ERGB
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Disease relevance of FLI1


High impact information on FLI1

  • This [6] indicates that the EWS-FLI1 fusion protein may act as an aberrant transcription factor, but the exact mechanism of oncogenesis remains unknown [1].
  • MFNG is also expressed in human tumour-derived cell lines expressing EWS/FLI1 [7].
  • Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation [8].
  • In PTS cells, the hemizygous deletion of FLI1 generates a subpopulation of CD41(+)CD42(-) cells completely lacking FLI1 transcription [2].
  • Provocative new data suggest that FLI1 shows monoallelic expression during a brief window in megakaryocyte differentiation, which thus explains the dominant inheritance pattern of PTS despite the presence of one normal FLI1 allele [9].
  • The role of Fli-1 in normal cell function and malignant transformation [10].

Chemical compound and disease context of FLI1


Biological context of FLI1

  • PTS patients harbor deletions on the long arm of chromosome 11, including the FLI1 gene, which encodes a transcription factor essential for megakaryopoiesis [2].
  • Addition of ETS1 and FLI1, two ETS family members that have homology in the 5' HLH region, but not Spi1, an ETS family member without the 5' HLH region, also inhibited reporter gene expression [13].
  • Ewing's family tumors (EFTs) are highly malignant tumors arising from bone and soft tissues that exhibit EWS-FLI1 or variant EWS-ETS gene fusions in more than 85% of the cases [14].
  • More than 85% of Ewing's family tumors carry a specific chromosomal translocation that fuses the NH(2) terminus of the EWS gene to the COOH terminus of the FLI1 transcription factor [15].
  • It has been shown previously that both the transactivation domain encoded by EWS and the DNA binding domain of FLI1 were necessary for transforming cells to anchorage independence [15].

Anatomical context of FLI1


Associations of FLI1 with chemical compounds

  • The effects of modulating genes involved in metabolism were assessed by flux studies and demonstrated shifts in glucose utilization and lactate production as a result of EWS/FLI1 expression [19].
  • In 85% of Ewing family tumors, the NH2 terminus of EWS is fused to the DNA-binding domain of FLI1, an ets transcription factor [20].
  • Up-regulation of uridine phosphorylase by EWS/FLI1 sensitizes cells to growth inhibition by the pyrimidine analogue, 5'-deoxy-5'fluorouridine, both in tissue culture and in vivo model systems [21].
  • Protein tyrosine phosphatase L1 (PTPL1) was identified as a gene upregulated by EWS-FLI1 in transfected cells by microarray [22].
  • Recombinant EWS-FLI1 protein under native conditions specifically binds to DNA and transcribes RNA [23].

Physical interactions of FLI1

  • We show that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity [24].
  • FEV encodes a 238 amino acid protein which contains an ETS DNA binding domain closely related to that of FLI-1 and ERG [25].
  • Furthermore, deletion of 194 amino terminal amino acids of FLI1 did not interfere with its ability to interact with SRF, in fact, this truncation increased the stability of the ternary complex [26].
  • As a result of acquired chromosome rearrangement, the N-terminal portion of the EWS protein is fused to the DNA binding domain of either FLI-1 or ERG in the Ewing family of tumors and to the DNA binding domain of ATF1 in malignant melanoma of soft parts [27].

Regulatory relationships of FLI1

  • Finally, the role of the ET-associated EWS-FLI1 fusion gene in regulating D cyclin expression was studied [28].
  • In addition, our data show that both ETS1 and FLI-1 strongly activate transcription of the GADD153 EBS linked to the CAT reporter gene [29].
  • Gene profiling of Ewing cells in which the EWS/FLI-1 fusion gene had been inactivated identified downstream targets which could be grouped in two major functional clusters related to extracellular matrix structure or remodeling and regulation of signal transduction pathways [24].
  • Both PIASxalpha/ARIP3 and the closely related PIASxbeta isoform specifically enhanced sumoylation of FLI-1 at Lys(67), located in its N-terminal activation domain [30].
  • We demonstrate that the N-terminus of TAFII68 efficiently stimulates transcription when fused to two different DNA binding domains and that overexpression of TAFII68-FLI-1 chimeras in NIH3T3 cells leads to oncogenic transformation [31].

Other interactions of FLI1

  • Expression microarray of case 1 revealed that three of these genes, FLI1, NFRKB, and SNX19, were also overexpressed [32].
  • Interestingly, the FLI1 homologous sequence contains a breakpoint of the t(11;22) translocation associated with Ewing's tumors, and may have a similar function in RUNX1 [33].
  • The tumorigenic potency of each EWS/ETS fusion is linked to its C-terminal structure, with the FLI1 C-terminus confering a greater tumorigenic potential than the corresponding ETV1 domain [34].
  • EWS-FLI1 was found to drive MK-STYX expression by binding to a single ETS binding motif within the first gene intron [3].
  • Suppression of the Ewing's sarcoma phenotype by FLI1/ERF repressor hybrids [35].

Analytical, diagnostic and therapeutic context of FLI1

  • FISH analysis on pre-mRNA and single-cell RT-PCR revealed that FLI1 expression is mainly monoallelic in CD41(+)CD42(-) progenitors, while it is predominantly biallelic in the other stages of megakaryopoiesis [2].
  • Standard and repeated fluorescence in situ hybridization and high-resolution cytometry were used to study topographical parameters of chromosome 11 and 22 territories, EWSR1 and FLI1 genes, and other genetic elements of these chromosomes in human lymphocytes and Ewing sarcoma cells [16].
  • In addition, we demonstrate that YAC B45C11 contains other transcribed sequences in addition to FLI1, by "cross-species" Northern blot hybridizations, which suggests the presence of additional genes in the immediate vicinity of the ES breakpoint on 11q24 [36].
  • Northern analysis and reverse transcriptase PCR reveal expression of EWS/FLI1 gene fusions in all biphenotypic sarcomas analyzed [37].
  • Chromatin immunoprecipitation assays reveal that EWS/FLI1 directly associates with the uridine phosphorylase promoter in vivo [21].






  1. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Hahm, K.B., Cho, K., Lee, C., Im, Y.H., Chang, J., Choi, S.G., Sorensen, P.H., Thiele, C.J., Kim, S.J. Nat. Genet. (1999) [Pubmed]
  2. FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia. Raslova, H., Komura, E., Le Couédic, J.P., Larbret, F., Debili, N., Feunteun, J., Danos, O., Albagli, O., Vainchenker, W., Favier, R. J. Clin. Invest. (2004) [Pubmed]
  3. EWS-FLI1 target genes recovered from Ewing's sarcoma chromatin. Siligan, C., Ban, J., Bachmaier, R., Spahn, L., Kreppel, M., Schaefer, K.L., Poremba, C., Aryee, D.N., Kovar, H. Oncogene (2005) [Pubmed]
  4. Absence of EWS/FLI1 fusion in olfactory neuroblastomas indicates these tumors do not belong to the Ewing's sarcoma family. Kumar, S., Perlman, E., Pack, S., Davis, M., Zhang, H., Meltzer, P., Tsokos, M. Hum. Pathol. (1999) [Pubmed]
  5. The human homolog of the mouse common viral integration region, FLI1, maps to 11q23-q24. Baud, V., Lipinski, M., Rassart, E., Poliquin, L., Bergeron, D. Genomics. (1991) [Pubmed]
  6. 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. Ben-David, Y., Giddens, E.B., Letwin, K., Bernstein, A. Genes. Dev. (1991) [Pubmed]
  7. EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic. May, W.A., Arvand, A., Thompson, A.D., Braun, B.S., Wright, M., Denny, C.T. Nat. Genet. (1997) [Pubmed]
  8. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Delattre, O., Zucman, J., Plougastel, B., Desmaze, C., Melot, T., Peter, M., Kovar, H., Joubert, I., de Jong, P., Rouleau, G. Nature (1992) [Pubmed]
  9. Lonely in Paris: when one gene copy isn't enough. Shivdasani, R.A. J. Clin. Invest. (2004) [Pubmed]
  10. The role of Fli-1 in normal cell function and malignant transformation. Truong, A.H., Ben-David, Y. Oncogene. (2000) [Pubmed]
  11. Regulatory role of mevalonate and N-linked glycosylation in proliferation and expression of the EWS/FLI-1 fusion protein in Ewing's sarcoma cells. Wang, M., Xie, Y., Girnita, L., Nilsson, G., Dricu, A., Wejde, J., Larsson, O. Exp. Cell Res. (1999) [Pubmed]
  12. Detection of EWS-FLI-1 fusion in Ewing's sarcoma/peripheral primitive neuroectodermal tumor by fluorescence in situ hybridization using formalin-fixed paraffin-embedded tissue. Kumar, S., Pack, S., Kumar, D., Walker, R., Quezado, M., Zhuang, Z., Meltzer, P., Tsokos, M. Hum. Pathol. (1999) [Pubmed]
  13. Functional characterization of ETV6 and ETV6/CBFA2 in the regulation of the MCSFR proximal promoter. Fears, S., Gavin, M., Zhang, D.E., Hetherington, C., Ben-David, Y., Rowley, J.D., Nucifora, G. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  14. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Kawamura-Saito, M., Yamazaki, Y., Kaneko, K., Kawaguchi, N., Kanda, H., Mukai, H., Gotoh, T., Motoi, T., Fukayama, M., Aburatani, H., Takizawa, T., Nakamura, T. Hum. Mol. Genet. (2006) [Pubmed]
  15. The COOH-terminal domain of FLI-1 is necessary for full tumorigenesis and transcriptional modulation by EWS/FLI-1. Arvand, A., Welford, S.M., Teitell, M.A., Denny, C.T. Cancer Res. (2001) [Pubmed]
  16. Arrangement of chromosome 11 and 22 territories, EWSR1 and FLI1 genes, and other genetic elements of these chromosomes in human lymphocytes and Ewing sarcoma cells. Taslerová, R., Kozubek, S., Lukásová, E., Jirsová, P., Bártová, E., Kozubek, M. Hum. Genet. (2003) [Pubmed]
  17. Gene expression profile of ewing sarcoma cell lines differing in their EWS-FLI1 fusion type. Bandrés, E., Malumbres, R., Escalada, A., Cubedo, E., González, I., Honorato, B., Zarate, R., García-Foncillas, J., de Alava, E. J. Pediatr. Hematol. Oncol. (2005) [Pubmed]
  18. EWS-FLI1 fusion protein up-regulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing's family of tumors. Hu-Lieskovan, S., Zhang, J., Wu, L., Shimada, H., Schofield, D.E., Triche, T.J. Cancer Res. (2005) [Pubmed]
  19. PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins. Deneen, B., Welford, S.M., Ho, T., Hernandez, F., Kurland, I., Denny, C.T. Mol. Cell. Biol. (2003) [Pubmed]
  20. Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway. Spahn, L., Petermann, R., Siligan, C., Schmid, J.A., Aryee, D.N., Kovar, H. Cancer Res. (2002) [Pubmed]
  21. Functional analysis of the EWS/ETS target gene uridine phosphorylase. Deneen, B., Hamidi, H., Denny, C.T. Cancer Res. (2003) [Pubmed]
  22. PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing's Sarcoma tumorigenesis. Abaan, O.D., Levenson, A., Khan, O., Furth, P.A., Uren, A., Toretsky, J.A. Oncogene (2005) [Pubmed]
  23. Recombinant EWS-FLI1 oncoprotein activates transcription. Uren, A., Tcherkasskaya, O., Toretsky, J.A. Biochemistry (2004) [Pubmed]
  24. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Prieur, A., Tirode, F., Cohen, P., Delattre, O. Mol. Cell. Biol. (2004) [Pubmed]
  25. A new member of the ETS family fused to EWS in Ewing tumors. Peter, M., Couturier, J., Pacquement, H., Michon, J., Thomas, G., Magdelenat, H., Delattre, O. Oncogene (1997) [Pubmed]
  26. 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. Watson, D.K., Robinson, L., Hodge, D.R., Kola, I., Papas, T.S., Seth, A. Oncogene (1997) [Pubmed]
  27. Cloning and chromosome localization of the mouse Ews gene. Plougastel, B., Mattei, M.G., Thomas, G., Delattre, O. Genomics (1994) [Pubmed]
  28. Selective usage of D-Type cyclins by Ewing's tumors and rhabdomyosarcomas. Zhang, J., Hu, S., Schofield, D.E., Sorensen, P.H., Triche, T.J. Cancer Res. (2004) [Pubmed]
  29. Regulation of the human stress response gene GADD153 expression: role of ETS1 and FLI-1 gene products. Seth, A., Giunta, S., Franceschil, C., Kola, I., Venanzoni, M.C. Cell Death Differ. (1999) [Pubmed]
  30. FLI-1 functionally interacts with PIASxalpha, a member of the PIAS E3 SUMO ligase family. van den Akker, E., Ano, S., Shih, H.M., Wang, L.C., Pironin, M., Palvimo, J.J., Kotaja, N., Kirsh, O., Dejean, A., Ghysdael, J. J. Biol. Chem. (2005) [Pubmed]
  31. The N-terminal domain of human TAFII68 displays transactivation and oncogenic properties. Bertolotti, A., Bell, B., Tora, L. Oncogene (1999) [Pubmed]
  32. Amplified, lost, and fused genes in 11q23-25 amplicon in acute myeloid leukemia, an array-CGH study. Tyybäkinoja, A., Saarinen-Pihkala, U., Elonen, E., Knuutila, S. Genes Chromosomes Cancer (2006) [Pubmed]
  33. Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1. Levanon, D., Glusman, G., Bangsow, T., Ben-Asher, E., Male, D.A., Avidan, N., Bangsow, C., Hattori, M., Taylor, T.D., Taudien, S., Blechschmidt, K., Shimizu, N., Rosenthal, A., Sakaki, Y., Lancet, D., Groner, Y. Gene (2001) [Pubmed]
  34. Divergent Ewing's sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells. Thompson, A.D., Teitell, M.A., Arvand, A., Denny, C.T. Oncogene (1999) [Pubmed]
  35. Suppression of the Ewing's sarcoma phenotype by FLI1/ERF repressor hybrids. Athanasiou, M., LeGallic, L., Watson, D.K., Blair, D.G., Mavrothalassitis, G. Cancer Gene Ther. (2000) [Pubmed]
  36. Cloning of the entire FLI1 gene, disrupted by the Ewing's sarcoma translocation breakpoint on 11q24, in a yeast artificial chromosome. Selleri, L., Giovannini, M., Romo, A., Zucman, J., Delattre, O., Thomas, G., Evans, G.A. Cytogenet. Cell Genet. (1994) [Pubmed]
  37. Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing's sarcoma EWS/FLI1 fusion gene. Sorensen, P.H., Shimada, H., Liu, X.F., Lim, J.F., Thomas, G., Triche, T.J. Cancer Res. (1995) [Pubmed]
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