The ets Family Member Tel Binds to the Fli-1 Oncoprotein and Inhibits Its Transcriptional Activity*
- Boguslaw A. Kwiatkowski‡§,
- L. Scot Bastian‡§,
- Thomas R. Bauer, Jr.‡§,
- Schickwann Tsai¶,
- Anna G. Zielinska-Kwiatkowskaठand
- Dennis D. Hickstein‡§‖
- From the ‡Medical Research Service, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, the¶Division of Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, and the §Divisions of Hematology and Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195
Abstract
The tel gene, recently shown to be translocated in a spectrum of acute and chronic human leukemias, belongs to the ets family of sequence-specific transcription factors. To determine the role of Tel in normal hematopoietic development, we used the tel gene as the bait in the yeast two-hybrid system to screen a hematopoietic stem cell library. Two partners were identified: Tel binds to itself, and Tel binds to the ets family member Fli-1. In vitroand in vivo assays confirmed these interactions. In transient transfection assays, Fli-1 transactivates megakaryocytic specific promoters, and Tel inhibits this effect of Fli-1. Transactivation studies using deletion mutants of Tel, and the Tel-AML-1 fusion protein, indicate that the helix-loop-helix domain of Tel only partially inhibits transactivation and that complete inhibition requires the full-length Tel molecule, including the DNA binding domain. The Tel and Fli-1 proteins are expressed early in hematopoiesis, and the inability of Tel fusion proteins such as Tel-AML-1 to counteract Fli-1 mediated transactivation may contribute to the malignant phenotype in human leukemias where this fusion protein is present.
Footnotes
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↵* 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.
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↵‖ To whom correspondence should be addressed: Medical Research (151), Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108. Tel.: 206-764-2705; Fax 206-764-2827.
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↵1 The abbreviations used are: ALL, acute lymphoblastic leukemia; HLH, helix-loop-helix; bp, base pair(s); PAGE, polyacrylamide gel electrophoresis; GST, glutathioneS-transferase; SCF, stem cell factor; PVDF, polyvinylidene difluoride; PCR, polymerase chain reaction.
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- Received March 6, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
