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J. Biol. Chem., Vol. 279, Issue 28, 29398-29408, July 9, 2004

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AML1/Runx1 Recruits Calcineurin to Regulate Granulocyte Macrophage Colony-stimulating Factor by Ets1 Activation^*

Hebin Liu, Magnus Holm, Xiao-Qi Xie, Magnus Wolf-Watz, and Thomas Grundström

From the Department of Molecular Biology, Umeå University, Umeå S-901 87, Sweden

Acute myeloid leukemia 1 (AML1), also denoted Runx1, is a transcription factor essential for hematopoiesis, and the AML1 gene is the most common target of chromosomal translocations in human leukemias. AML1 binds to sequences present in the regulatory regions of a number of hematopoiesis-specific genes, including certain cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) up-regulated after T cell receptor stimulation. Here we show that both subunits of the Ca²⁺/calmodulin-dependent protein phosphatase calcineurin (CN), which is activated upon T cell receptor stimulation, interact directly with the N-terminal runt homology domain-containing part of AML1. The regulatory CN subunit binds AML1 with a higher affinity and in addition also interacts with the isolated runt homology domain. The related Runx2 transcription factor, which is essential for bone formation, also interacts with CN. A constitutively active derivative of CN is shown to activate synergistically the GM-CSF promoter/enhancer together with AML1 or Runx2. We also provide evidence that relief of the negative effect of the AML1 sites is important for Ca²⁺ activation of the GM-CSF promoter/enhancer and that AML1 overexpression increases this Ca²⁺ activation. Both subunits of CN interact with AML1 in coimmunoprecipitation analyses, and confocal microscopy analysis of cells expressing fluorescence-tagged protein derivatives shows that CN can be recruited to the nucleus by AML1 in vivo. Mutant analysis of the GM-CSF promoter shows that the Ets1 binding site of the promoter is essential for the synergy between AML1 and CN in Jurkat T cells. Analysis of the effects of inhibitors of the protein kinase glycogen synthase kinase-3 and in vitro phosphorylation/dephosphorylation analysis of Ets1 suggest that glycogen synthase kinase-3-phosphorylated Ets1 is a target of AML1-recruited CN phosphatase at the GM-CSF promoter.

Received for publication, March 22, 2004

^* This work was supported by grants from the Swedish Cancer Society, the Swedish Research Council, the Cancer Research Foundation in Umeå, and the Swedish Society of Medical Research. 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.

To whom correspondence should be addressed. Tel.: 46-90-785-2531; Fax: 46-90-771-420; E-mail: thomas.grundstrom{at}molbiol.umu.se.

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