The Mammalian Basic Helix Loop Helix Protein HES-1 Binds to and Modulates the Transactivating Function of the Runt-related Factor Cbfa1*
- Keith W. McLarren‡,
- Rita Lo‡,
- Diane Grbavec‡,
- Kannan Thirunavukkarasu§¶,
- Gerard Karsenty§ and
- Stefano Stifani‡‖
- From the ‡Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4 Canada and the §Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030
Abstract
Drosophila Runt is the founding member of a family of related transcription factors involved in the regulation of a variety of cell-differentiation events in invertebrates and vertebrates. Runt-related proteins act as both transactivators and transcriptional repressors, suggesting that context-dependent mechanisms modulate their transcriptional properties. The aim of this study was to elucidate the molecular mechanisms that contribute to the regulation of the functions of the mammalian Runt-related protein, Cbfa1. Here we provide the first demonstration that Cbfa1 (as well as the related protein, Cbfa2/AML1) physically interacts with the basic helix loop helix transcription factor, HES-1, a mammalian counterpart of the DrosophilaHairy and Enhancer of split proteins. This interaction is mediated by the carboxyl-terminal domains of Cbfa1 and HES-1, but does not require their respective tetrapeptide motifs, WRPY and WRPW. Our studies also show that HES-1 can antagonize the binding of Cbfa1 to mammalian transcriptional corepressors of the Groucho family. Moreover, HES-1 can potentiate Cbfa1-mediated transactivation in transfected cells. Taken together, these findings implicate HES-1 in the transcriptional functions of Cbfa1 and suggest that the concerted activities of Groucho and HES proteins modulate the functions of mammalian Runt-related proteins.
Footnotes
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↵* This work was supported by National Institutes of Health Grants DE11290 and HD97006 and a Basic Science Award of the March of Dimes Foundation (to G. K.) and Medical Research Council of Canada Grants MT-13957 and GR-14971 (to S. S.).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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↵¶ Present address: Endocrine Research, DC 0403, Lilly Research Labs, Indianapolis, IN 46285.
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↵‖ Scholar of the Fonds de la Recherche en Sante du Quebec and Killam Scholar of the Montreal Neurological Institute. To whom correspondence should be addressed: Tel.: 514-398-3946; Fax: 514-398-1319; E-mail: mdst@musica.mcgill.ca.
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↵2 K. McLarren, R. Lo, and S. Stifani, unpublished data.
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↵3 W. F. Wang and B. Olsen, personal communication.
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↵4 J. Yao, E. Lai, and S. Stifani, unpublished data.
- Abbreviations:
- Cbfa
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core binding factor α
- AML
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acute myeloid leukemia
- GAL4ad
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activation domain of GAL4
- GAL4bd
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DNA-binding domain of GAL4
- GST
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glutathioneS-transferase
- HES
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Hairy and Enhancer of split
- PAGE
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polyacrylamide gel electrophoresis
- TLE
-
transducin-like Enhancer of split
- WDR
-
WD40 repeat
- PCR
-
polymerase chain reaction
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- Received June 3, 1999.
- Revision received October 4, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
