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J. Biol. Chem., Vol. 280, Issue 17, 16625-16634, April 29, 2005

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Transcriptional Co-activators CREB-binding Protein/p300 Increase Chondrocyte Cd-rap Gene Expression by Multiple Mechanisms Including Sequestration of the Repressor CCAAT/Enhancer-binding Protein^*

Toshihiro Imamura, Chisako Imamura, Yukihide Iwamoto, and Linda J. Sandell¶||

From the Departments of Orthopaedic Surgery and ^¶Cell Biology and Physiology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110 and the Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

Cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a small secreted matrix protein expressed in developing and adult cartilage and by chondrocytes in culture. We have previously shown that the expression of Cd-rap, like many other cartilage matrix proteins, is repressed by interleukin 1 and that the transcription factor CCAAT/enhancer-binding protein (C/EBP) plays an important role in the interleukin 1-induced repression (Okazaki, K., Li, J., Yu, H., Fukui, N., and Sandell, L. J. (2002) J. Biol. Chem. 277, 31526–31533). The co-activators CREB-binding protein (CBP) and p300 are transcriptional co-regulators that participate in the activities of many different transcription factors including C/EBP. Here we show that CBP/p300 can reverse the inhibitory effect of C/EBP and moreover can stimulate expression of Cd-rap. The mechanism of this effect is shown to involve a unique synergy whereby CBP/p300 stimulate Cd-rap gene expression by at least two mechanisms. First, binding of CBP/p300 to C/EBP leads to sequestration of C/EBP eliminating DNA binding and subsequent repression; second, binding of CBP/p300 to the transcriptional activator Sox9 increases Sox9 DNA binding to the Cd-rap promoter leading to further stimulation of gene transcription. This is an example of a complementary transcriptional network whereby two very different mechanisms act together to confer a functional increase in transcription. This new paradigm is likely generally applicable to cartilage genes as Col2a1 cartilage collagen gene responds similarly.

Received for publication, October 7, 2004 , and in revised form, February 14, 2005.

^* This work was supported by NIAMS, National Institutes of Health Grants R01 AR36994 and R01 AR045550. 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: Dept. of Orthopaedic Surgery, Washington University School of Medicine at Barnes-Jewish Hospital, 660 S. Euclid Ave., Box 8233, St. Louis, MO 63110. Tel.: 314-454-7800; Fax: 314-454-5900; E-mail: sandelll{at}wustl.edu.

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