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J. Biol. Chem., Vol. 278, Issue 52, 52032-52041, December 26, 2003

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Transcriptional Activation of Mouse Mast Cell Protease-7 by Activin and Transforming Growth Factor- Is Inhibited by Microphthalmia-associated Transcription Factor^*

Masayuki Funaba, Teruo Ikeda¶, Masaru Murakami||, Kenji Ogawa**, Kunihiro Tsuchida, Hiromu Sugino, and Matanobu Abe

From the Laboratories of Nutrition and ^||Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 229-8501, ^¶Azabu University Research Institute of Biosciences, Sagamihara 229-8501, ^**Laboratory of Cellular Biochemistry, RIKEN, Wako 351-0198, and Institute for Enzyme Research, the University of Tokushima, Tokushima 770-8503, Japan

Previous studies have revealed that activin A and transforming growth factor-₁ (TGF-₁) induced migration and morphological changes toward differentiation in bone marrow-derived cultured mast cell progenitors (BMCMCs). Here we show up-regulation of mouse mast cell protease-7 (mMCP-7), which is expressed in differentiated mast cells, by activin A and TGF-₁ in BMCMCs, and the molecular mechanism of the gene induction of mmcp-7. Smad3, a signal mediator of the activin/TGF- pathway, transcriptionally activated mmcp-7. Microphthalmia-associated transcription factor (MITF), a tissue-specific transcription factor predominantly expressed in mast cells, melanocytes, and heart and skeletal muscle, inhibited Smad3-mediated mmcp-7 transcription. MITF associated with Smad3, and the C terminus of MITF and the MH1 and linker region of Smad3 were required for this association. Complex formation between Smad3 and MITF was neither necessary nor sufficient for the inhibition of Smad3 signaling by MITF. MITF inhibited the transcriptional activation induced by the MH2 domain of Smad3. In addition, MITF-truncated N-terminal amino acids could associate with Smad3 but did not inhibit Smad3-mediated transcription. The level of Smad3 was decreased by co-expression of MITF but not of dominant-negative MITF, which resulted from proteasomal protein degradation. The changes in the level of Smad3 protein were paralleled by those in Smad3-mediated signaling activity. These findings suggest that MITF negatively regulates Smad-dependent activin/TGF- signaling in a tissue-specific manner.

Received for publication, July 1, 2003 , and in revised form, October 2, 2003.

^* This work was supported by Grants-in-aid for Scientific Research 13760214 and 15580268 from Japan Society for the Promotion of Science (to M. F.) and grants for Graduate Schools from the Foundation for Japanese Private School Promotion (to T. I.). 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: Laboratory of Nutrition, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Sagamihara 229-8501, Japan. Tel.: 81-42-754-7111 (ext. 276); Fax: 81-42-754-9930; E-mail: funaba{at}azabu-u.ac.jp.

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