| Co-Investigator(Kenkyū-buntansha) |
YASUMOTO Ken-ichi School of Medicine, Tohoku University, Research Associate, 大学院・医学系研究科, 助手 (90241629)
TAKAHASHI Kazuhiro School of Medicine, Tohoku University, Associate Professor, 大学院・医学系研究科, 助教授 (80241628)
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| Research Abstract |
Microphthalmia-associated transcription factor (MITF) affects the development of many types of cells, including neural-crest derived melanocytes and optic cup-derived retinal pigment epithelium (RPE). MITF consists of at least four isoforms, MITF-A, MITF-H, MITF-B and MITF-M, differing at their amino-termini and expression patterns. These four isoforms share the entire carboxyl-terminal portion, including a basic helix-loop-helix and leucine zipper structure, and function as transcriptional activators, as judged by transient transfection assay. The human MITF gene contains at least four isoform-specific first exons, exons 1A, 1H, 1B, and 1M in the 5' to 3' direction, each of which encodes the unique amino-terminus of a given isoform. The 5'-flanking regions of these isoform-specific exons are termed promoters A, H, B, and M, respectively, which showed different promoter activities. Promoter A directs the expression of a reporter gene in RPE, cervical cancer, and melanoma cells, whereas
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promoter M is functional only in melanoma cells. Promoter H showed the significant activity in RPE and cervical cancer cells but not in melanoma cells. In contrast, the 1.7-kb 5'-flanking region of exon 1B showed no noticeable promoter activity in these cell lines. Therefore, alternative promoters provide the MITF gene with the diversity in transcriptional regulation and the capability of generating structurally different protein isoforms.
In addition, the following results have been obtained. 1. We have identified a fifth MITF isoform MITF-C, which differs in the amino-terminus and expression patterns. 2. Black-eyed white MitfィイD1mi-bwィエD1 mice are characterized by the complete white coat color and inner ear deafness due to lack of melanocytes and by normally pigmented RPE. The molecular lesion of MitfィイD1mi-bwィエD1 mice has been identified as the insertion of an L1 retrotransposable element in the intron 3 between exon 3 and exon 4, leading to complete repression of Mitf-M mRNA expression and to different levels of reduction of Mitf-A and Mitf-H mRNAs expression. Thus, Mitf-M is indispensable for the normal development of melanocytes but not RPE. Less
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