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J. Biol. Chem., Vol. 278, Issue 32, 30148-30156, August 8, 2003

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Hox Proteins Functionally Cooperate with the GC Box-binding Protein System through Distinct Domains^*

Mitsuko Suzuki  , Naoto Ueno ¶ and Atsushi Kuroiwa  ||

From the Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602 and the ^¶Department of Developmental Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Japan

Hox genes encode a transcriptional factor that plays a key role in regulating position-specific cartilage pattern formation. We found that Hoxa-13 and Hoxd-13, which are members of the Abd-B subfamily of Hox genes and are crucial for the autopod development of the limb, stimulate transcription from the Bmp-4 promoter. This stimulation was dependent on the GC box within the promoter and independent of the putative Hox protein binding site. The stimulation by HoxA-13 was remarkably enhanced by cotransfection with members of a family of zinc finger GC box binding transcriptional factors including Sp1. The stimulation was suppressed by another Abd-B Hox protein, HoxA-11, indicating that each Abd-B Hox protein has a different effect on the target genes through the Sp1 system. We have identified multiple functional domains involved in transcriptional regulation, including three independent transcriptional activation domains (ADs) in HoxA-13. AD1 and AD3 in helices 1 and 2 of the homeodomain individually cooperate with Sp1-dependent stimulation. The homeodomain is also required for cooperation of the AD with Sp1. By contrast, AD2 strongly activates transcription in an Sp1-independent manner only when the homeodomain has been removed. These observations indicate that HoxA-13 regulates transcription through multiple pathways. In addition, we found that a helix 3 mutation of the HoxA-13 homeodomain behaves as a dominant negative form.

Received for publication, April 15, 2003

^* This work was supported by the Monbu Kagakusyo "Priority Areas Research (A) Developmental System" (to A. K.). 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.

Supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

^|| To whom correspondence should be addressed. Tel.: 81-52-789-2994; Fax: 81-52-789-2995; E-mail: i45240a{at}nucc.cc.nagoya-u.ac.jp.

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