Transcriptional activation of mouse mast cell Protease-7 by activin and transforming growth factor-beta is inhibited by microphthalmia-associated transcription factor.
Previous studies have revealed that activin A and transforming growth factor-beta1 (TGF-beta1) 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-beta1 in BMCMCs, and the molecular mechanism of the gene induction of mmcp-7. Smad3, a signal mediator of the activin/TGF-beta 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-beta signaling in a tissue-specific manner.
Funaba
Masayuki
M
Laboratory of Nutrition, Azabu University School of Veterinary Medicine, Sagamihara 229-8501, Japan. funaba@azabu-u.ac.jp
Ikeda
Teruo
T
Murakami
Masaru
M
Ogawa
Kenji
K
Tsuchida
Kunihiro
K
Sugino
Hiromu
H
Abe
Matanobu
M
D028341:Activins / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051739:Microphthalmia-Associated Transcription Factor; D041681:NIH 3T3 Cells; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053802:Tryptases; D015854:Up-Regulation
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D011994:Recombinant Proteins; C509190:Tpsb2 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D028341:Activins; D012313:RNA; D008156:Luciferases; D012697:Serine Endopeptidases; C509222:Tpsab1 protein, mouse; D053802:Tryptases