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J. Biol. Chem., Vol. 279, Issue 38, 39895-39904, September 17, 2004

This Article Full Text Full Text (PDF) Suplemental Data All Versions of this Article: 279/38/39895    most recent M404132200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, W. Articles by Largman, C. Search for Related Content PubMed PubMed Citation Articles by Shen, W. Articles by Largman, C. Social Bookmarking                      What's this?

HOXB6 Protein Is Bound to CREB-binding Protein and Represses Globin Expression in a DNA Binding-dependent, PBX Interaction-independent Process^*

Weifang Shen, Daniel Chrobak, Keerthi Krishnan, H. Jeffrey Lawrence, and Corey Largman

From the Department of Medicine, University of California Veterans Affairs Medical Center, San Francisco, California 94121

Although HOXB6 and other HOX genes have previously been associated with hematopoiesis and leukemias, the precise mechanism of action of their protein products remains unclear. Here we use a biological model in which HOXB6 represses - and -globin mRNA levels to perform a structure/function analysis for this homeodomain protein. HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion. However, the capacity to form cooperative DNA-binding complexes with the PBX co-factor protein is not required for HOXB6 biological activity. Neither the conserved extreme N-terminal region, a polyglutamic acid region at the protein C terminus, nor the Ser²¹⁴ CKII phosphorylation site was required for DNA binding or activity in this model. We have previously reported that HOX proteins can inhibit CREB-binding protein (CBP)-histone acetyltransferase-mediated potentiation of reporter gene transcription. We now show that endogenous CBP is co-precipitated with exogenous HOXB6 from nuclear and cytoplasmic compartments of transfected K562 cells. Furthermore, endogenous CBP co-precipitates with endogenous HOXB6 in day 14.5 murine fetal liver cells during active globin gene expression in this tissue. The CBP interaction motif was localized to the homeodomain but does not require the highly conserved helix 3. Our data suggest that the homeodomain contains most or all of the important structures required for HOXB6 activity in blood cells.

Received for publication, April 14, 2004 , and in revised form, July 9, 2004.

^* This work was supported by funds from the Department of Veterans Affairs (to C. L.) and National Institutes of Health Grants GM55814 and CA80029 (to C. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental tables.

To whom correspondence should be addressed: Molecular Hematopoiesis Research, VA Medical Center, 4150 Clement St., San Francisco, CA 94121. Tel.: 415-750-2254; Fax: 415-750-6959; E-mail: largman{at}cgl.ucsf.edu.

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