Transcriptional regulation of plasminogen activator inhibitor-1 by transforming growth factor-β, activin A and microphthalmia-associated transcription factor

• Published in: Cellular signalling 2006-02, Vol.18 (2), p.256-265
• Main Authors: Murakami, Masaru, Ikeda, Teruo, Saito, Taiju, Ogawa, Kenji, Nishino, Yoshii, Nakaya, Kohei, Funaba, Masayuki
• Format: Article
• Language: English
• Subjects: Activin; Activins - pharmacology; Animals; Cell Line; Cells, Cultured; E-Box Elements; Inhibin-beta Subunits - pharmacology; Mast cell; Mast Cells - drug effects; Mast Cells - metabolism; Melanocyte; Melanocytes - drug effects; Melanocytes - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microphthalmia-associated transcription factor; Microphthalmia-Associated Transcription Factor - metabolism; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen activator inhibitor-1; Protein Isoforms - metabolism; RNA, Messenger - metabolism; Transcriptional Activation; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1; Transforming growth factor-β
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2005.04.010

Plasminogen activator inhibitor-1 ( PAI-1) is a key molecule that regulates turnover of the extracellular matrix. In the present study, we characterized PAI-1 gene expression in mast cells and melanocytes. In bone marrow-derived cultured mast cells, up-regulation of the PAI-1 gene was observed upon treatment with TGF-β 1, and was regulated at the transcriptional level. Microphthalmia-associated transcription factor (MITF), a member of the basic helix–loop–helix leucine zipper family of tissue-specific transcription factors predominantly expressed in mast cells, melanocytes and osteoclasts, also stimulated PAI-1 gene transcription, and TGF-β 1 did not increase PAI-1 mRNA levels in mast cells from mi/ mi mice expressing dominant-negative MITF. MITF isoforms regulated TGF-β 1-induced transcription of PAI-1 differently; MITF-E-mediated transcription was further increased by TGF-β 1, whereas transcriptional activation by TGF-β 1 was blocked by MITF-M or MITF-mc expression. In contrast, activin A, another member of the TGF-β family, enhanced transcription induced by MITF-M, as well as by MITF-E, although MITF-mc blocked activin A-induced transcription of PAI-1. Different regulation of PAI-1 gene expression upon TGF-β 1 and activin A treatment was also detected in B16 melanocytes; TGF-β 1 transiently increased the PAI-1 mRNA level, whereas activin A had prolonged effects on up-regulation of PAI-1. Our results on the control of PAI-1 gene expression by MITF isoforms, TGF-β 1 and activin A suggest that discrete regulation of the plasminogen activator system occurs in a cell type-specific manner.