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J. Biol. Chem., Vol. 281, Issue 35, 25659-25669, September 1, 2006

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Identification of an N-terminal Transactivation Domain of Runx1 That Separates Molecular Function from Global Differentiation Function^*

Hebin Liu, Leif Carlsson¹, and Thomas Grundström²

From the Department of Molecular Biology and Umeå Center for Molecular Medicine, Umeå University, SE-901 87 Umeå, Sweden

RUNX1, or AML1, is a transcription factor that is the most frequent target for chromosomal gene translocations in acute leukemias. RUNX1 is essential for definitive hematopoiesis in embryos and profoundly influences adult steady-state hematopoiesis both positively and negatively. To investigate this wide range of normal activities and the pathological role of RUNX1, it is important to define the functions of different domains of the protein. RUNX1, RUNX2, and RUNX3 are highly conserved in their DNA binding runt homology domain and contain divergent sequences of unknown function N-terminal to this domain. Here we analyzed the role of the N-terminal sequence and the -helix of the runt homology domain of Runx1 in DNA binding, transactivation, and megakaryocytopoiesis. Both the N terminus and the -helix were found to reduce DNA binding of Runx1 and be essential for transactivation of the granulocyte-macrophage colony-stimulating factor and I1 promoters by Runx1. The N terminus of Runx1, including the -helix, was also required for transactivation of a Gal4 reporter when expressed as fusion proteins with a Gal4 DNA binding domain, and the N terminus alone was capable of stimulating transcription when fused to the Gal4 DNA binding domain. The N terminus and the -helix, however, were not required for megakaryocyte development from embryonic stem cells differentiated in vitro. Thus, our findings define a second transactivation domain of Runx1 that is differentially required for activation of transcription of some Runx1-dependent promoters and megakaryocytopoiesis.

Received for publication, April 5, 2006 , and in revised form, June 26, 2006.

^* This work was supported in part by grants from the Swedish Cancer Society (to T. G. and L. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Tobias Foundation.

² To whom correspondence should be addressed. Tel.: 46-90-7852531; Fax: 46-90-771420; E-mail: Thomas.Grundstrom{at}molbiol.umu.se.

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