| Co-Investigator(Kenkyū-buntansha) |
ADACHI Shiro Osaka Univ Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40301254)
ITO Akihiko Osaka Univ Graduate School of Medicine Assist, Profess, 医学系研究科, 助手 (80273647)
JIPPO Tomoko Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70252658)
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| Research Abstract |
MITF is a basic-helix-loop-helix leucine zipper (bHLH-Zip) transcription factor, which is important for the development of mast cells. The mi locus encoding MITF possesses various mutant alleles. These are useful for examining the structure-function relationship of MITF in vivo. Mast cells of mi/mi genotype express normal amount of abnormal MITF (mi-MITF), whereas mast cells of tg/tg genotype do not express any MITFs. Mast cells of mi/mi mice show more severe abnormalities than those of tg/tg mice, indicating that the mi-MITF possesses the inhibitory function. The MITF encoded by the mi^<ce> mutant allele (ce-MITF) lacks the Zip domain. We examined the importance of the Zip domain using mi^<ce>/mi^<ce> mice. The amounts of c-kit, granzyme B (Gr B), and tryptophan hydroxylase (TPH) mRNAs decreased in mast cells of mi^<ce>/mi^<ce> mice to levels comparable to those of tg/tg mice, and the amounts were intermediate between those of +/+ mice and those of mi/mi mice. Gr B mediates the cytotoxic activity of mast cells, and TPH is a rate-limiting enzyme for the synthesis of serotonin. The cytotoxic activity and serotonin content of mi^<ce>/mi^<ce> mast cells were comparable to those of tg/tg mast cells, and were significantly higher than those of mi/mi mast cells. The phenotype of mi^<ce>/mi^<ce> mast cells was similar to that of tg/tg mast cells rather than to that of mi/mi mast cells, suggesting that the ce-MITF had no functions. The Zip domain of MITF appeared to be important for the development of mast cells. We also revealed that MITF played an important role in the transcription of mouse mast cell protease (mMCP)-6, -7, alpha-melanocyte stimulating hormone receptor, N-deacetylase N-sulfotransferase 2 genes. MITF regulated their transcription through the interaction of other transcription factors, such as PEBP2/CBF, c-Jun and GABP.MITF appeared to play a crucial role in the transcriptional regulation of mast cell specific genes.
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