Lee M, Goodall J, Verastegui C, Ballotti R, Goding C R
Eukaryotic Transcription Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, United Kingdom.
J Biol Chem. 2000 Dec 1;275(48):37978-83. doi: 10.1074/jbc.M003816200.
The transcription factor Sox10 is genetically linked with Waardenburg syndrome 4 (WS4) in humans and the Dominant megacolon (Dom) mouse model for this disease. The pigmentary defects observed in the Dom mouse and WS4 are reminiscent of those associated with mutations in the microphthalmia (Mitf) gene, which encodes a transcription factor essential for the development of the melanocyte lineage. We demonstrate here that wild type Sox10 directly binds and activates transcription of the MITF promoter, whereas a mutant form of the Sox10 protein genetically linked with WS4 acts as a dominant-negative repressor of MITF expression and can reduce endogenous MITF protein levels. The ability of Sox10 to activate transcription of the MITF promoter implicates Sox10 in the regulation of melanocyte development and provides a molecular basis for the hypopigmentation and deafness associated with WS4.
转录因子Sox10在人类中与瓦登伯革氏综合征4型（WS4）以及该疾病的显性巨结肠（Dom）小鼠模型存在基因关联。在Dom小鼠和WS4中观察到的色素沉着缺陷让人联想到与小眼畸形（Mitf）基因突变相关的缺陷，Mitf基因编码一种对黑素细胞谱系发育至关重要的转录因子。我们在此证明，野生型Sox10直接结合并激活MITF启动子的转录，而与WS4存在基因关联的Sox10蛋白突变形式则作为MITF表达的显性负性抑制剂，可降低内源性MITF蛋白水平。Sox10激活MITF启动子转录的能力表明Sox10参与黑素细胞发育的调控，并为与WS4相关的色素减退和耳聋提供了分子基础。
