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DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma.

Laboratoire d'Oncologie Virale et Cellulaire, Centre National de la Recherche Scientifique, URA 1443, Institut Curie, Orsay, France.

ABSTRACT

The 5' half of the EWS gene has recently been described to be fused to the 3' regions of genes encoding the DNA-binding domain of several transcriptional regulators, including ATF1, FLI-1, and ERG, in several human tumors. The most frequent occurrence of this situation results from the t(11;22)(q24;q12) chromosome translocation specific for Ewing sarcoma (ES) and related tumors which joins EWS sequences to the 3' half of FLI-1, which encodes a member of the Ets family of transcriptional regulators. We show here that this chimeric gene encodes an EWS-FLI-1 nuclear protein which binds DNA with the same sequence specificity as the wild-type parental FLI-1 protein. We further show that EWS-FLI-1 is an efficient sequence-specific transcriptional activator of model promoters containing FLI-1 (Ets)-binding sites, a property which is strictly dependent on the presence of its EWS domain. Comparison of the properties of the N-terminal activation domain of FLI-1 to those of the EWS domain of the fusion protein indicates that EWS-FLI-1 has altered transcriptional activation properties compared with FLI-1. These results suggest that EWS-FLI-1 contributes to the transformed phenotype of ES tumor cells by inducing the deregulated and/or unscheduled activation of genes normally responsive to FLI-1 or to other close members of the Ets family. ES and related tumors are characterized by an elevated level of c-myc expression. We show that EWS-FLI-1 is a transactivator of the c-myc promoter, suggesting that upregulation of c-myc expression is under control of EWS-FLI-1.

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• Torchia, E. C., Boyd, K., Rehg, J. E., Qu, C., Baker, S. J. (2007). EWS/FLI-1 Induces Rapid Onset of Myeloid/Erythroid Leukemia in Mice. Mol. Cell. Biol. 27: 7918-7934 [Abstract] [Full Text]  
• Slater, O., Shipley, J. (2007). Clinical relevance of molecular genetics to paediatric sarcomas. J. Clin. Pathol. 60: 1187-1194 [Abstract] [Full Text]  
• Carrillo, J., Garcia-Aragoncillo, E., Azorin, D., Agra, N., Sastre, A., Gonzalez-Mediero, I., Garcia-Miguel, P., Pestana, A., Gallego, S., Segura, D., Alonso, J. (2007). Cholecystokinin Down-Regulation by RNA Interference Impairs Ewing Tumor Growth. Clin. Cancer Res. 13: 2429-2440 [Abstract] [Full Text]  
• Mateo-Lozano, S., Gokhale, P. C., Soldatenkov, V. A., Dritschilo, A., Tirado, O. M., Notario, V. (2006). Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma.. Clin. Cancer Res. 12: 6781-6790 [Abstract] [Full Text]  
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• Riggi, N., Cironi, L., Provero, P., Suva, M.-L., Kaloulis, K., Garcia-Echeverria, C., Hoffmann, F., Trumpp, A., Stamenkovic, I. (2005). Development of Ewing's Sarcoma from Primary Bone Marrow-Derived Mesenchymal Progenitor Cells. Cancer Res. 65: 11459-11468 [Abstract] [Full Text]  
• 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. (2005). FLI-1 Functionally Interacts with PIASx{alpha}, a Member of the PIAS E3 SUMO Ligase Family. J. Biol. Chem. 280: 38035-38046 [Abstract] [Full Text]  
• Castillero-Trejo, Y., Eliazer, S., Xiang, L., Richardson, J. A., Ilaria, R. L. Jr. (2005). Expression of the EWS/FLI-1 Oncogene in Murine Primary Bone-Derived Cells Results in EWS/FLI-1-Dependent, Ewing Sarcoma-Like Tumors. Cancer Res. 65: 8698-8705 [Abstract] [Full Text]  
• Hu-Lieskovan, S., Heidel, J. D., Bartlett, D. W., Davis, M. E., Triche, T. J. (2005). Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma. Cancer Res. 65: 8984-8992 [Abstract] [Full Text]  
• Nozawa, S., Ohno, T., Banno, Y., Dohjima, T., Wakahara, K., Fan, D.-G., Shimizu, K. (2005). Inhibition of Platelet-derived Growth Factor-induced Cell Growth Signaling by a Short Interfering RNA for EWS-Fli1 via Down-regulation of Phospholipase D2 in Ewing Sarcoma Cells. J. Biol. Chem. 280: 27544-27551 [Abstract] [Full Text]  
• Jinnin, M., Ihn, H., Mimura, Y., Asano, Y., Yamane, K., Tamaki, K. (2005). Matrix metalloproteinase-1 up-regulation by hepatocyte growth factor in human dermal fibroblasts via ERK signaling pathway involves Ets1 and Fli1. Nucleic Acids Res 33: 3540-3549 [Abstract] [Full Text]  
• Zhang, X. K., Watson, D. K. (2005). The FLI-1 Transcription Factor Is a Short-Lived Phosphoprotein in T Cells. J Biochem 137: 297-302 [Abstract] [Full Text]  
• Prieur, A., Tirode, F., Cohen, P., Delattre, O. (2004). 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. Mol. Cell. Biol. 24: 7275-7283 [Abstract] [Full Text]  
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• Burchill, S A (2003). Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J. Clin. Pathol. 56: 96-102 [Abstract] [Full Text]  
• Eliazer, S., Spencer, J., Ye, D., Olson, E., Ilaria, R. L. Jr. (2003). Alteration of Mesodermal Cell Differentiation by EWS/FLI-1, the Oncogene Implicated in Ewing's Sarcoma. Mol. Cell. Biol. 23: 482-492 [Abstract] [Full Text]  
• de Alava, E., Pardo, J. (2001). Ewing Tumor: Tumor Biology and Clinical Applications. INT J SURG PATHOL 9: 7-17 [Abstract]  
• Buijs, A., van Rompaey, L., Molijn, A. C., Davis, J. N., Vertegaal, A. C. O., Potter, M. D., Adams, C., van Baal, S., Zwarthoff, E. C., Roussel, M. F., Grosveld, G. C. (2000). The MN1-TEL Fusion Protein, Encoded by the Translocation (12;22)(p13;q11) in Myeloid Leukemia, Is a Transcription Factor with Transforming Activity. Mol. Cell. Biol. 20: 9281-9293 [Abstract] [Full Text]  
• Liu, J., Nau, M. M., Yeh, J. C., Allegra, C. J., Chu, E., Wright, J. J. (2000). Molecular Heterogeneity and Function of EWS-WT1 Fusion Transcripts in Desmoplastic Small Round Cell Tumors. Clin. Cancer Res. 6: 3522-3529 [Abstract] [Full Text]  
• Spyropoulos, D. D., Pharr, P. N., Lavenburg, K. R., Jackers, P., Papas, T. S., Ogawa, M., Watson, D. K. (2000). Hemorrhage, Impaired Hematopoiesis, and Lethality in Mouse Embryos Carrying a Targeted Disruption of the Fli1 Transcription Factor. Mol. Cell. Biol. 20: 5643-5652 [Abstract] [Full Text]  
• Xiao, S., McCarthy, J. G., Aster, J. C., Fletcher, J. A. (2000). ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain. Blood 96: 699-704 [Abstract] [Full Text]  
• Sarrazin, S., Starck, J., Gonnet, C., Doubeikovski, A., Melet, F., Morle, F. (2000). Negative and Translation Termination-Dependent Positive Control of FLI-1 Protein Synthesis by Conserved Overlapping 5' Upstream Open Reading Frames in Fli-1 mRNA. Mol. Cell. Biol. 20: 2959-2969 [Abstract] [Full Text]  
• de Alava, E., Gerald, W. L. (2000). Molecular Biology of the Ewing’s Sarcoma/Primitive Neuroectodermal Tumor Family. JCO 18: 204-204 [Abstract] [Full Text]  
• Lopez, R. G., Carron, C., Oury, C., Gardellin, P., Bernard, O., Ghysdael, J. (1999). TEL Is a Sequence-specific Transcriptional Repressor. J. Biol. Chem. 274: 30132-30138 [Abstract] [Full Text]  
• Inoue, K., Roussel, M. F., Sherr, C. J. (1999). Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. Proc. Natl. Acad. Sci. USA 96: 3993-3998 [Abstract] [Full Text]  
• Bertolotti, A., Melot, T., Acker, J., Vigneron, M., Delattre, O., Tora, L. (1998). EWS, but Not EWS-FLI-1, Is Associated with Both TFIID and RNA Polymerase II: Interactions between Two Members of the TET Family, EWS and hTAFII68, and Subunits of TFIID and RNA Polymerase II Complexes. Mol. Cell. Biol. 18: 1489-1497 [Abstract] [Full Text]  
• Powers, C. A., Mathur, M., Raaka, B. M., Ron, D., Samuels, H. H. (1998). TLS (Translocated-in-Liposarcoma) Is a High-Affinity Interactor for Steroid, Thyroid Hormone, and Retinoid Receptors. Mol. Endocrinol. 12: 4-18 [Abstract] [Full Text]  
• Toretsky, J. A., Kalebic, T., Blakesley, V., LeRoith, D., Helman, L. J. (1997). The Insulin-like Growth Factor-I Receptor Is Required for EWS/FLI-1 Transformation of Fibroblasts. J. Biol. Chem. 272: 30822-30827 [Abstract] [Full Text]  
• Doubeikovski, A., Uzan, G., Doubeikovski, Z., Prandini, M.-H., Porteu, F., Gisselbrecht, S., Dusanter-Fourt, I. (1997). Thrombopoietin-induced Expression of the Glycoprotein IIb Gene Involves the Transcription Factor PU.1/Spi-1 in UT7-Mpl Cells. J. Biol. Chem. 272: 24300-24307 [Abstract] [Full Text]  
• Serdobova, I., Pla, M., Reichenbach, P., Sperisen, P., Ghysdael, J., Wilson, A., Freeman, J., Nabholz, M. (1997). Elf-1 Contributes to the Function of the Complex Interleukin (IL)-2-responsive Enhancer in the Mouse IL-2 Receptor alpha  Gene. J. Exp. Med. 185: 1211-1222 [Abstract] [Full Text]  
• Markiewicz, S., Bosselut, R., Deist, F. L., Villartay, J.-P. d., Hivroz, C., Ghysdael, J., Fischer, A., Basile, G. d. S. (1996). Tissue-specific Activity of the gamma c Chain Gene Promoter Depends upon an Ets Binding Site and Is Regulated by GA-binding Protein. J. Biol. Chem. 271: 14849-14855 [Abstract] [Full Text]  
• Zinszner, H, Albalat, R, Ron, D (1994). A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP.. Genes Dev. 8: 2513-2526 [Abstract]  
• Knoop, L. L., Baker, S. J. (2000). The Splicing Factor U1C Represses EWS/FLI-mediated Transactivation. J. Biol. Chem. 275: 24865-24871 [Abstract] [Full Text]  
• Bojovic', B. B., Hassell, J. A. (2001). The PEA3 Ets Transcription Factor Comprises Multiple Domains That Regulate Transactivation and DNA Binding. J. Biol. Chem. 276: 4509-4521 [Abstract] [Full Text]  
• Yang, L., Chansky, H. A., Hickstein, D. D. (2000). EWS{middle dot}Fli-1 Fusion Protein Interacts with Hyperphosphorylated RNA Polymerase II and Interferes with Serine-Arginine Protein-mediated RNA Splicing. J. Biol. Chem. 275: 37612-37618 [Abstract] [Full Text]  
• Lerga, A., Hallier, M., Delva, L., Orvain, C., Gallais, I., Marie, J., Moreau-Gachelin, F. (2001). Identification of an RNA Binding Specificity for the Potential Splicing Factor TLS. J. Biol. Chem. 276: 6807-6816 [Abstract] [Full Text]  
• Czuwara-Ladykowska, J., Shirasaki, F., Jackers, P., Watson, D. K., Trojanowska, M. (2001). Fli-1 Inhibits Collagen Type I Production in Dermal Fibroblasts via an Sp1-dependent Pathway. J. Biol. Chem. 276: 20839-20848 [Abstract] [Full Text]  
• Uranishi, H., Tetsuka, T., Yamashita, M., Asamitsu, K., Shimizu, M., Itoh, M., Okamoto, T. (2001). Involvement of the Pro-oncoprotein TLS (Translocated in Liposarcoma) in Nuclear Factor-kappa B p65-mediated Transcription as a Coactivator. J. Biol. Chem. 276: 13395-13401 [Abstract] [Full Text]  
• KIM, J., PELLETIER, J. (1999). Molecular genetics of chromosome translocations involving EWS and related family members. Physiol. Genomics 1: 127-138 [Abstract] [Full Text]