Identification of aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF
Identification of aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF
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DOI：
10.1074/jbc.m110229200
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发表时间：
2002-01-04
影响因子：
4.8
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
Du, JY;Fisher, DE
动物色素突变体为研究从黑素细胞发育到黑色素瘤的基因调控途径提供了丰富的模型。一种小鼠模型是白色基因座，其等位基因表现出眼睛和皮毛的色素沉着改变，有时以年龄依赖性的方式。在这里，我们表明，最近确定的基因突变产生日本金色的鱼，青鳉B，映射到小鼠的基因座的小鼠同源物。我们确定了这个基因的不同突变，被称为目的-1，在三个underwhite小鼠等位基因，并发现结构/功能差异与隐性与显性遗传。AIM-1的人类直系同源物最初被鉴定为黑素细胞限制性抗原，其被来自黑素瘤患者的自体T细胞识别。我们还提供了证据表明，AIM-1是转录调制的MITF，黑素细胞特异性转录因子必不可少的色素沉着和人类黑色素瘤的临床诊断标志物。虽然AIM-1似乎位于MITF的下游，但染色质免疫沉淀没有显示MITF与含有组蛋白3乙酰化的5 '侧翼区域结合，表明MITF要么间接作用于AIM-1，要么与远程调控序列结合。然而，MITF连接AIM-1的表达和underwhite表型的转录网络中央色素沉着的哺乳动物。
Animal pigmentation mutants have provided rich models for the identification of genes modulating pathways from melanocyte development to melanoma. One mouse model is the underwhite locus, alleles of which manifest altered pigmentation of both eye and fur, sometimes in an age-dependent fashion. Here we show that the mouse homolog of a recently identified gene whose mutation produces Japanese gold-colored fish, medaka b, maps to the mouse underwhite locus. We identify distinct mutations of this gene, known as Aim-1, in three underwhite mouse alleles and find that structure/function differences correlate with recessive versus dominant inheritance. The human ortholog of AIM-1 was originally identified as a melanocyte-restricted antigen that is recognized by autologous T cells from a patient with melanoma. We also provide evidence that AIM-1 is transcriptionally modulated by MITF, a melanocyte-specific transcription factor essential to pigmentation and a clinical diagnostic marker in human melanoma. Although AIM-1 appears to reside downstream of MITF, chromatin immunoprecipitations do not reveal binding of MITF to a 5'-flanking region containing histone 3 acetylation, indicating that MITF either acts indirectly on AIM-1 or it binds to a remote regulatory sequence. Nevertheless, MITF links AIM-1 expression and the underwhite phenotype to a transcriptional network central to pigmentation in mammals.