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J. Biol. Chem., Vol. 281, Issue 25, 16870-16878, June 23, 2006

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Transcriptional Regulation of the Xenopus laevis Stromelysin-3 Gene by Thyroid Hormone Is Mediated by a DNA Element in the First Intron^*

Liezhen Fu¹, Akihiro Tomita¹², Hua Wang, Daniel R. Buchholz, and Yun-Bo Shi³

From the Section on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, NICHD, National Institutes of Health, Bethesda, Maryland 20892 and Department of Food Science and Technology, Ohio State University, Columbus, Ohio 43210

The matrix metalloproteinase (MMP) stromelysin-3 (ST3) (MMP11) was first isolated as a breast cancer-associated gene and is expressed in diverse human carcinomas and various developmental processes involving apoptosis. The Xenopus laevis ST3 is highly up-regulated by thyroid hormone (T3) during amphibian metamorphosis, and its expression is spatially and temporally correlated with apoptosis in different tissues. Furthermore, it has been shown in vivo and in organ cultures to play a critical role in regulating T3-induced epithelial cell death during intestinal metamorphosis. Earlier studies suggest that ST3 is a direct T3 response gene, although a thyroid hormone response element (TRE) was not found in the initial analysis of the ST3 promoter. Here, we have identified a strong TRE consisting of two nearly perfect direct repeats of the consensus nuclear hormone receptor binding element AGGTCA separated by 4 bp in the first intron of the Xenopus ST3 gene. We show that the heterodimers of T3 receptor (TR) and 9-cis-retinoic acid receptor bind to the TRE both in vitro and in vivo in the context of chromatin. Furthermore, T3 induces strong activation of the promoter through the intronic TRE. Interestingly, although the unliganded TR/9-cis-retinoic acid receptor was able to recruit corepressors to the promoter, it had little repressive effect on the promoter in vivo. These results suggest that the intronic TRE mediates the inductive effect of T3 and that promoter context plays an important role in gene repression by unliganded TR.

Received for publication, March 30, 2006

^* This research was supported by the Intramural Research Program of the NICHD, National Institutes of Health. 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 Fig. S1.

¹ These authors are equal contributors.

² Present address: Dept. of Infectious Diseases, Nagoya University School of Medicine, Tsurumai-Cho 65, Showa-ku, Nagoya 466-8560, Japan.

³ To whom correspondence should be addressed: Bldg. 18 T, Rm. 106 LGRD, NICHD, National Institutes of Health Bethesda, MD, 20892. Tel.: 301-402-1004; Fax: 301-402-1323; E-mail: shi{at}helix.nih.gov.

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				S. Mathew, L. Fu, M. Fiorentino, H. Matsuda, B. Das, and Y.-B. Shi Differential Regulation of Cell Type-specific Apoptosis by Stromelysin-3: A POTENTIAL MECHANISM VIA THE CLEAVAGE OF THE LAMININ RECEPTOR DURING TAIL RESORPTION IN XENOPUS LAEVIS J. Biol. Chem., July 3, 2009; 284(27): 18545 - 18556. [Abstract] [Full Text] [PDF]

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