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Gene Review

FLII  -  flightless I homolog (Drosophila)

Homo sapiens

Synonyms: FLI, FLIL, Fli1, MGC39265, Protein flightless-1 homolog
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Disease relevance of FLII

  • Ewing's sarcoma, a highly malignant neoplasm, is characterized by an 11;22 translocation [t(11;22) (q24;q12)], resulting in the fusion of genes FLII and EWS [1].
  • In vitro, cells derived from Ewing sarcoma (ES) with the characteristic somatic rearrangement between the genes EWS and FLII can be induced to differentiate toward a neuronal phenotype by exposure to agents such as dibutyryl cyclic AMP (db cAMP) or retinoic acid [2].
  • The secondary structure of the ets domain of human Fli-1 resembles that of the helix-turn-helix DNA-binding motif of the Escherichia coli catabolite gene activator protein [3].
  • In addition, Fli-1 binding of the GPIX Ets site was identified in antibody supershift experiments in nuclear extracts derived from hematopoietic human erythroleukemia cells [4].
  • Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state [5].

High impact information on FLII

  • Here we use these fragments to screen human complementary DNA libraries to show that the translocation alters the open reading frame of an expressed gene on chromosome 22 gene by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the human homologue of murine Fli-1 [6].
  • T cells express multiple members of the Ets gene family including Ets-1, Ets-2, GABP alpha, Elf-1, and Fli-1 [7].
  • Co-transfection experiments in Q2bn fibroblasts showed cooperative activation of the EOS47 proximal promoter by c-Myb, Ets-1/Fli-1, GATA-1 and C/EBPalpha [8].
  • The Ets-1/Fli-1 and C/EBPalpha proteins were the most potent activators, and acted with high synergy through juxtaposed binding sites located approximately 60 bp upstream of the transcription start site [8].
  • Southern blot analysis of somatic-cell hybrids and/or FISH analysis of lymphoblastoid cell lines from 12 SMS patients demonstrates the deletion of one copy of FLI in all SMS patients analyzed [9].

Biological context of FLII


Anatomical context of FLII

  • Skeletal and cardiac muscles are particularly rich in the 3.3-kb FLAP message, and the FLI message as well [12].
  • FLI has a C-terminal gelsolin-like domain which binds actin and therefore the association of TRIP with the FLI LRR may provide a link between the actin cytoskeleton and RNA in mammalian cells [13].
  • MATERIALS AND METHODS: RT-PCR assays for the EWS-FLII, EWS-ERG, PAX3-FKHR, PAX7-FKHR, and EWS-WTI fusion transcripts were performed on RNA extracted from the primary tumor tissue, bone marrow, and body fluids obtained at initial presentation and relapse [14].
  • In addition, expression of Fli-1 was identified immunohistochemically in megakaryocytes derived from CD34(+) cells treated with the megakaryocyte differentiation and proliferation factor, thrombopoietin [4].
  • To test the effect on endogenous genes, we stably overexpressed Fli-1 in K562 cells, a line rich in GATA-1 [15].

Associations of FLII with chemical compounds

  • CONCLUSIONS: Molecular detection of EWS-Fli1 fusion transcripts in formalin-fixed paraffin-embedded material by nested RT-PCR is feasible and is useful for the diagnosis and differential diagnosis of ES/pPNETs [16].
  • Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1 [4].
  • These reciprocal functional interactions extended to other nuclear receptors such as thyroid hormone and retinoic acid receptors, as well as to Fli1, an ERG-related ETS factor [17].
  • In this report, we show that the recombinant Fli-1 protein expressed in bacteria binds to DNA in a sequence-specific manner [18].
  • Functional interference between retinoic acid or steroid hormone receptors and the oncoprotein Fli-1 [19].

Physical interactions of FLII


Regulatory relationships of FLII


Other interactions of FLII

  • We report the identification of two related genes, LRRFIP1 and LRRFIP2, encoding proteins that interact with the LRR domain of human FLI using the yeast two-hybrid system [24].
  • We present two patients with SMS who have interstitial deletions at 17p11.2 but are not deleted for currently available commercial FISH probes that include FLII; both patients have deletions that are demonstrated with probes containing the RAI1 gene [25].
  • Fli-1 and CD99 were detected in 90% and 55% of cases, respectively [26].
  • The involvement of the ET-specific fusion transcript EWS/Fli-1 in modulating the HLA-A and -B locus antigens is likely to occur by the upregulation of c-myc in these tumors [27].
  • Here we report the physical interaction of Fli-1 with GATA-1, a well-characterized, zinc finger transcription factor critical for both erythroid and megakaryocytic differentiation [15].

Analytical, diagnostic and therapeutic context of FLII


  1. Adamantinoma-like Ewing's sarcoma: genomic confirmation, phenotypic drift. Bridge, J.A., Fidler, M.E., Neff, J.R., Degenhardt, J., Wang, M., Walker, C., Dorfman, H.D., Baker, K.S., Seemayer, T.A. Am. J. Surg. Pathol. (1999) [Pubmed]
  2. Expression and regulation of the transcriptional repressor ZNF43 in Ewing sarcoma cells. González-Lamuño, D., Loukili, N., García-Fuentes, M., Thomson, T.M. Pediatric pathology & molecular medicine. (2002) [Pubmed]
  3. The secondary structure of the ets domain of human Fli-1 resembles that of the helix-turn-helix DNA-binding motif of the Escherichia coli catabolite gene activator protein. Liang, H., Olejniczak, E.T., Mao, X., Nettesheim, D.G., Yu, L., Thompson, C.B., Fesik, S.W. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  4. Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1. Bastian, L.S., Kwiatkowski, B.A., Breininger, J., Danner, S., Roth, G. Blood (1999) [Pubmed]
  5. The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors. Rorie, C.J., Thomas, V.D., Chen, P., Pierce, H.H., O'Bryan, J.P., Weissman, B.E. Cancer Res. (2004) [Pubmed]
  6. 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]
  7. Evolutionarily conserved Ets family members display distinct DNA binding specificities. Wang, C.Y., Petryniak, B., Ho, I.C., Thompson, C.B., Leiden, J.M. J. Exp. Med. (1992) [Pubmed]
  8. Regulation of eosinophil-specific gene expression by a C/EBP-Ets complex and GATA-1. McNagny, K.M., Sieweke, M.H., Döderlein, G., Graf, T., Nerlov, C. EMBO J. (1998) [Pubmed]
  9. The human homologue of the Drosophila melanogaster flightless-I gene (flil) maps within the Smith-Magenis microdeletion critical region in 17p11.2. Chen, K.S., Gunaratne, P.H., Hoheisel, J.D., Young, I.G., Miklos, G.L., Greenberg, F., Shaffer, L.G., Campbell, H.D., Lupski, J.R. Am. J. Hum. Genet. (1995) [Pubmed]
  10. Fliih, a gelsolin-related cytoskeletal regulator essential for early mammalian embryonic development. Campbell, H.D., Fountain, S., McLennan, I.S., Berven, L.A., Crouch, M.F., Davy, D.A., Hooper, J.A., Waterford, K., Chen, K.S., Lupski, J.R., Ledermann, B., Young, I.G., Matthaei, K.I. Mol. Cell. Biol. (2002) [Pubmed]
  11. Genomic structure, evolution, and expression of human FLII, a gelsolin and leucine-rich-repeat family member: overlap with LLGL. Campbell, H.D., Fountain, S., Young, I.G., Claudianos, C., Hoheisel, J.D., Chen, K.S., Lupski, J.R. Genomics (1997) [Pubmed]
  12. Identification of the binding partners for flightless I, A novel protein bridging the leucine-rich repeat and the gelsolin superfamilies. Liu, Y.T., Yin, H.L. J. Biol. Chem. (1998) [Pubmed]
  13. TRIP: a novel double stranded RNA binding protein which interacts with the leucine rich repeat of flightless I. Wilson, S.A., Brown, E.C., Kingsman, A.J., Kingsman, S.M. Nucleic Acids Res. (1998) [Pubmed]
  14. Use of reverse transcriptase polymerase chain reaction for diagnosis and staging of alveolar rhabdomyosarcoma, Ewing sarcoma family of tumors, and desmoplastic small round cell tumor. Athale, U.H., Shurtleff, S.A., Jenkins, J.J., Poquette, C.A., Tan, M., Downing, J.R., Pappo, A.S. J. Pediatr. Hematol. Oncol. (2001) [Pubmed]
  15. Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding. Eisbacher, M., Holmes, M.L., Newton, A., Hogg, P.J., Khachigian, L.M., Crossley, M., Chong, B.H. Mol. Cell. Biol. (2003) [Pubmed]
  16. Molecular detection of EWS-Ets fusion transcripts and their clinicopathologic significance in Ewing's sarcoma/peripheral primitive neuroectodermal tumor. Wang, H., Zheng, J., Wang, Y.P., Yang, Y., You, J.F. Chin. Med. J. (2005) [Pubmed]
  17. Mutual repression of transcriptional activation between the ETS-related factor ERG and estrogen receptor. Vlaeminck-Guillem, V., Vanacker, J.M., Verger, A., Tomavo, N., Stehelin, D., Laudet, V., Duterque-Coquillaud, M. Oncogene (2003) [Pubmed]
  18. Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein. Rao, V.N., Ohno, T., Prasad, D.D., Bhattacharya, G., Reddy, E.S. Oncogene (1993) [Pubmed]
  19. Functional interference between retinoic acid or steroid hormone receptors and the oncoprotein Fli-1. Darby, T.G., Meissner, J.D., Rühlmann, A., Mueller, W.H., Scheibe, R.J. Oncogene (1997) [Pubmed]
  20. The ets family member Tel binds to the Fli-1 oncoprotein and inhibits its transcriptional activity. Kwiatkowski, B.A., Bastian, L.S., Bauer, T.R., Tsai, S., Zielinska-Kwiatkowska, A.G., Hickstein, D.D. J. Biol. Chem. (1998) [Pubmed]
  21. Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway. Czuwara-Ladykowska, J., Shirasaki, F., Jackers, P., Watson, D.K., Trojanowska, M. J. Biol. Chem. (2001) [Pubmed]
  22. Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1. Ramakrishnan, R., Fujimura, Y., Zou, J.P., Liu, F., Lee, L., Rao, V.N., Reddy, E.S. Oncogene (2004) [Pubmed]
  23. Ets factors regulate the polycystic kidney disease-1 promoter. Puri, S., Rodova, M., Islam, M.R., Magenheimer, B.S., Maser, R.L., Calvet, J.P. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  24. Novel proteins interacting with the leucine-rich repeat domain of human flightless-I identified by the yeast two-hybrid system. Fong, K.S., de Couet, H.G. Genomics (1999) [Pubmed]
  25. Diagnostic FISH probes for del(17)(p11.2p11.2) associated with Smith-Magenis syndrome should contain the RAI1 gene. Vlangos, C.N., Wilson, M., Blancato, J., Smith, A.C., Elsea, S.H. Am. J. Med. Genet. A (2005) [Pubmed]
  26. Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Llombart, B., Monteagudo, C., López-Guerrero, J.A., Carda, C., Jorda, E., Sanmartín, O., Almenar, S., Molina, I., Martín, J.M., Llombart-Bosch, A. Histopathology (2005) [Pubmed]
  27. Monomorphic HLA class I-(non-A, non-B) expression on Ewing's tumor cell lines, modulation by TNF-alpha and IFN-gamma. Borowski, A., van Valen, F., Ulbrecht, M., Weiss, E.H., Blasczyk, R., Jürgens, H., Göbel, U., Schneider, E.M. Immunobiology (1999) [Pubmed]
  28. Structure and expression of human Fli-1 gene. Prasad, D.D., Rao, V.N., Reddy, E.S. Cancer Res. (1992) [Pubmed]
  29. The Ews/Fli-1 fusion gene changes the status of p53 in neuroblastoma tumor cell lines. Rorie, C.J., Weissman, B.E. Cancer Res. (2004) [Pubmed]
  30. Ets-dependent regulation of target gene expression during megakaryopoiesis. Jackers, P., Szalai, G., Moussa, O., Watson, D.K. J. Biol. Chem. (2004) [Pubmed]
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