Transcriptional regulation of plasminogen activator inhibitor-1 by transforming growth factor-beta, activin A and microphthalmia-associated transcription factor.
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-beta1, 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-beta1 did not increase PAI-1 mRNA levels in mast cells from mi/mi mice expressing dominant-negative MITF. MITF isoforms regulated TGF-beta1-induced transcription of PAI-1 differently; MITF-E-mediated transcription was further increased by TGF-beta1, whereas transcriptional activation by TGF-beta1 was blocked by MITF-M or MITF-mc expression. In contrast, activin A, another member of the TGF-beta 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-beta1 and activin A treatment was also detected in B16 melanocytes; TGF-beta1 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-beta1 and activin A suggest that discrete regulation of the plasminogen activator system occurs in a cell type-specific manner.
Murakami
Masaru
M
Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 229-8501, Japan.
Ikeda
Teruo
T
Saito
Taiju
T
Ogawa
Kenji
K
Nishino
Yoshii
Y
Nakaya
Kohei
K
Funaba
Masayuki
M
D028341:Activins / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D024721:E-Box Elements; D028322:Inhibin-beta Subunits / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D051739:Microphthalmia-Associated Transcription Factor; D017395:Plasminogen Activator Inhibitor 1; D020033:Protein Isoforms; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits