Steingrímsson Eiríkur, Copeland Neal G, Jenkins Nancy A
Department of Biochemistry and Molecular Biology, University of Iceland, 101 Reykjavik, Iceland.
Annu Rev Genet. 2004;38:365-411. doi: 10.1146/annurev.genet.38.072902.092717.
The first mouse microphthalmia transcription factor (Mitf ) mutation was discovered over 60 years ago, and since then over 24 spontaneous and induced mutations have been identified at the locus. Mitf encodes a member of the Myc supergene family of basic helix-loop-helix zipper (bHLH-Zip) transcription factors. Like Myc, Mitf regulates gene expression by binding to DNA as a homodimer or as a heterodimer with another related family member, in the case of Mitf the Tfe3, Tfeb, and Tfec proteins. The study of Mitf has provided many insights into the biology of melanocytes and helped to explain how melanocyte-specific gene expression and signaling is regulated. The human homologue of MITF is mutated in patients with the pigmentary and deafness disorder Waardenburg Syndrome Type 2A (WS2A). The mouse Mitf mutations therefore serve as a model for the study of this human disease. Mutations and/or aberrant expression of several MITF family member genes have also been reported in human cancer, including melanoma (MITF), papillary renal cell carcinoma (TFE3, TFEB), and alveolar soft part sarcoma (TFE3). Genes in the MITF/TFE pathway may therefore also represent valuable therapeutic targets for the treatment of human cancer. Here we review recent developments in the analysis of Mitf function in vivo and in vitro and show how traditional genetics, modern forward genetics and in vitro biochemical analyses have combined to produce an intriguing story on the role and actions of a gene family in a living organism.
60多年前首次发现了小鼠小眼畸形转录因子（Mitf）突变，自那时起，在该基因座已鉴定出超过24种自发和诱导突变。Mitf编码碱性螺旋-环-螺旋拉链（bHLH-Zip）转录因子的Myc超基因家族的一个成员。与Myc一样，Mitf通过作为同二聚体或与另一个相关家族成员（对于Mitf而言，是Tfe3、Tfeb和Tfec蛋白）形成异二聚体与DNA结合来调节基因表达。对Mitf的研究为黑素细胞生物学提供了许多见解，并有助于解释黑素细胞特异性基因表达和信号传导是如何被调控的。MITF的人类同源物在患有色素沉着和耳聋疾病2A型瓦登伯革综合征（WS2A）的患者中发生突变。因此，小鼠Mitf突变可作为研究这种人类疾病的模型。在人类癌症中也报道了几种MITF家族成员基因的突变和/或异常表达，包括黑色素瘤（MITF）、乳头状肾细胞癌（TFE3、TFEB）和肺泡软组织肉瘤（TFE3）。因此，MITF/TFE途径中的基因也可能代表治疗人类癌症的有价值的治疗靶点。在这里，我们综述了体内和体外Mitf功能分析的最新进展，并展示了传统遗传学、现代正向遗传学和体外生化分析如何结合起来，揭示了一个基因家族在生物体中的作用和行为的有趣故事。
