Transcriptional regulation of mouse mast cell protease-7 by TGF-β

Mouse mast cell protease-7 (mmcp-7) is a tryptase predominantly expressed in differentiated connective tissue-type mast cells. Previous study revealed that transforming growth factor-β (TGF-β) increases gene transcript of mmcp-7 in mast cells. The present study explored molecular mechanism of the up-regulation of mmcp-7 by TGF-β. Luciferase-based reporter assays using deletion and point mutations of mmcp-7 promoter showed a critical region spanning nt − 126 to − 122 relative to the transcriptional start site, a Smad-binding element, for transcriptional activation by the TGF-β pathway. In addition, a region from nt − 104 to − 98, a TPA-responsive element, was also necessary for the transactivation. Consistent with the current model for the TGF-β signaling, Smad4 was required for the transcription of mmcp-7 by Smad3, a signal mediator of TGF-β. Treatment with TGF-β in mast cells resulted in the differential gene induction of the AP-1 components, i.e., transient induction of c-fos but not of c-jun and junB. Expression of c-fos further enhanced Smad3 and Smad4-induced transcription of mmcp-7, whereas c-jun expression inhibited the transcription. Our results suggest that TGF-β stimulates mmcp-7 transcription through the Smad3-Smad4 pathway as well as c-fos induction, and that the AP-1 components distinctly related with the TGF-β pathway.