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J. Biol. Chem., Vol. 279, Issue 20, 20626-20635, May 14, 2004

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Interaction between Hex and GATA Transcription Factors in Vascular Endothelial Cells Inhibits flk-1/KDR-mediated Vascular Endothelial Growth Factor Signaling^*

Takashi Minami¶, Takeshi Murakami, Keiko Horiuchi, Mai Miura, Tamio Noguchi||, Jun-ichi Miyazaki**, Takao Hamakubo, William C. Aird, and Tatsuhiko Kodama

From the Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo, 153-8904 Japan, the ^||Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8604 Japan, the ^**Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka 565-0871 Japan, and the Department of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts 02215

Recent evidence supports a role for GATA transcription factors as important signal intermediates in differentiated endothelial cells. The goal of this study was to identify proteins that interact with endothelial-derived GATA transcription factors. Using yeast two-hybrid screening, we identified hematopoietically expressed homeobox (Hex) as a GATA-binding partner in endothelial cells. The physical association between Hex and GATA was confirmed with immunoprecipitation in cultured cells. Hex overexpression resulted in decreased flk-1/KDR expression, both at the level of the promoter and the endogenous gene, and attenuated vascular endothelial growth factor-mediated tube formation in primary endothelial cell cultures. In electrophoretic mobility shift assays, Hex inhibited the binding of GATA-2 to the flk-1/KDR 5'-untranslated region GATA motif. Finally, in RNase protection assays, transforming growth factor 1, which has been previously shown to decrease flk-1 expression by interfering with GATA binding activity, was shown to increase Hex expression in endothelial cells. Taken together, the present study provides evidence for a novel association between Hex and GATA and suggests that transforming growth factor -mediated repression of flk-1/KDR and vascular endothelial growth factor signaling involves the inducible formation of inhibitory Hex-GATA complexes.

Received for publication, August 7, 2003 , and in revised form, March 10, 2004.

^* This work was supported by funds from the Uehara Memorial Foundation in Japan (to T. M.). 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.

These authors contributed equally to this work.

Supported in part by National Institutes of Health Grants HL 60585-03, HL 63609-02, and HL 65216-02.

^¶ To whom correspondence should be addressed: Research Center for Advanced Science and Technology, the University of Tokyo, 4-6-1 Komaba, Meguro Tokyo, 153-8904. Tel.: 81-3-5452-5403; Fax: 81-3-5452-5232; E-mail: minami{at}med.rcast.u-tokyo.ac.jp.

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