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Originally published In Press as doi:10.1074/jbc.M106757200 on September 11, 2001

J. Biol. Chem., Vol. 276, Issue 45, 41977-41984, November 9, 2001
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DNA Binding Domain-independent Pathways Are Involved in EWS/FLI1-mediated Oncogenesis*

Scott M. WelfordDagger , Stephen P. Hebert§, Benjamin DeneenDagger , Afsane Arvand, and Christopher T. DennyDagger §||**

From the Dagger  Molecular Biology Institute, the § Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, and the  Department of Experimental Pathology and Laboratory Medicine, || Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095

Specific chromosomal translocations involving the ews gene and one of five members of the ets family of transcription factors create ews/ets fusion genes that are found in ~85% of Ewing's family of tumors. ews/ets fusion genes consistently maintain an intact and functional ets DNA binding domain (DBD) in all of these cases. We demonstrate here, however, that EWS/FLI1, the most prevalent EWS/ETS fusion, activates oncogenic pathways independent of its DBD. In in vivo tumor assays, EWS/FLI1 molecules with either point mutations or a large deletion in the ets DBD retain the ability to accelerate tumors in NIH 3T3 cells, whereas they lose the ability to bind DNA in vitro. Additionally, whereas inhibition of DBD functions of EWS/FLI1 with a dominant negative form of FLI1 is sufficient to inhibit anchorage-independent growth in NIH 3T3 cells, it is ineffective in inhibiting tumor growth in SCID mice. Usage of this dominant negative construct in a Ewing's tumor cell line, however, does reduce the rate of tumor formation, supporting the need for a functional DBD in this context. Together, these results suggest that EWS/FLI1 induces both DBD-dependent and DBD-independent oncogenic pathways.

* This work was supported by NCI Grants CA32737 and CA87771 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed. Tel.: 310-825-0704; Fax: 310-206-8089, E-mail: cdenny@ucla.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.