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J. Biol. Chem., Vol. 282, Issue 23, 16846-16859, June 8, 2007

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Identification of a HoxA10 Activation Domain Necessary for Transcription of the Gene Encoding 3 Integrin during Myeloid Differentiation^*

Ling Bei, YuFeng Lu, Susan L. Bellis^¶, Wei Zhou, Elizabeth Horvath, and Elizabeth A. Eklund¹

From the Fineberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, Jesse Brown Veterans Health Administration Hospital, Chicago, Illinois 60612, and the ^¶Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294-2070

Transcription of the ITGB3 gene, which encodes 3 integrin, increases during myeloid differentiation. v3 integrin mediates adhesion to fibronectin or vitronectin and regulates various aspects of the inflammatory response in mature phagocytes. In these studies, we found that the homeodomain transcription factor HoxA10 interacted with a specific ITGB3 cis element and activated transcription of this gene during myeloid differentiation. We also found that increased fibronectin adhesion in differentiating myeloid cells was dependent upon this HoxA10-induced increase in 3 integrin expression. We determined that activation of ITGB3 transcription required a HoxA10 domain that was not identical to the "hexapeptide" that mediates interaction of Hox and Pbx proteins. This activation domain was also not identical to a previously identified HoxA10 repression domain that mediates interaction with transcriptional co-repressors. Instead, this HoxA10 activation domain had homology to "PQ" protein-protein interaction domains that have been described previously in other transcription factors. Consistent with this, we found that the HoxA10 PQ-like domain recruited the CREB-binding protein (CBP) to the ITGB3 promoter. This was associated with an increase in local histone acetylation in vivo. In immature myeloid cells, we previously determined that HoxA10 repressed transcription of the CYBB and NCF2 genes, which encode the phagocyte oxidase proteins gp91^PHOX and p67^PHOX, respectively. Therefore, our studies indicated that HoxA10 either activates or represses gene transcription at various points during myelopoiesis. Our studies also suggested that HoxA10 is a bifunctional protein that is involved in dynamic regulation of multiple aspects of phagocyte phenotype and function.

Received for publication, October 17, 2006 , and in revised form, April 12, 2007.

^* 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 To whom correspondence should be addressed: Dept. of Medicine, Feinberg School at Northwestern University, 710 N. Fairbanks Ct., Olson 8524, Chicago, IL, 60611. Tel.: 312-503-4625; E-mail: e-eklund{at}northwestern.edu.

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