Pérez-Mancera Pedro Antonio, Pérez-Losada Jesus, Sánchez-Martín Manuel, Rodríguez-García Maria Aranzazu, Flores Teresa, Battaner Enrique, Gutiérrez-Adán Alfonso, Pintado Belen, Sánchez-García Isidro
Instituto de Biologia Molecular y Celular del Cancer, Centro de Investigacion del Cancer, CSIC/Universidad de Salamanca, Campus Unamuno 37007-Salamanca, Spain.
Oncogene. 2002 Mar 7;21(11):1679-84. doi: 10.1038/sj.onc.1205220.
Fusion proteins created by chromosomal abnormalities are key components of mesenchymal cancer development. The most common chromosomal translocation in liposarcomas, t(12;16)(q13;p11), creates the FUS-CHOP fusion gene. In the past, we generated FUS-CHOP and CHOP transgenic mice and have shown that while FUS-CHOP transgenic develop liposarcomas, mice expressing CHOP, which lacks the FUS domain, display essentially normal white adipose tissue (WAT) development, suggesting that the FUS domain of FUS-CHOP plays a specific and critical role in the pathogenesis of liposarcoma. To test the significance of FUS and CHOP domain interactions within a living mouse, we generated mice expressing the FUS domain and crossed them with CHOP-transgenic mice to generate double-transgenic FUSxCHOP animals. Here we report that expression of the FUS domain restores liposarcoma development in CHOP-transgenic mice. Our results provide genetic evidence that FUS and CHOP domains function in trans for the mutual restoration of liposarcoma. These results identify a new mechanism of tumor-associated fusion genes and might have impact beyond myxoid liposarcoma.
由染色体异常产生的融合蛋白是间充质癌发展的关键组成部分。脂肪肉瘤中最常见的染色体易位，即t(12;16)(q13;p11)，产生了FUS-CHOP融合基因。过去，我们构建了FUS-CHOP和CHOP转基因小鼠，并表明虽然FUS-CHOP转基因小鼠会发生脂肪肉瘤，但表达缺乏FUS结构域的CHOP的小鼠，其白色脂肪组织（WAT）发育基本正常，这表明FUS-CHOP的FUS结构域在脂肪肉瘤的发病机制中发挥着特定且关键的作用。为了在活体小鼠中测试FUS和CHOP结构域相互作用的重要性，我们构建了表达FUS结构域的小鼠，并将它们与CHOP转基因小鼠杂交，以产生双转基因FUSxCHOP动物。在此我们报告，FUS结构域的表达恢复了CHOP转基因小鼠中的脂肪肉瘤发展。我们的结果提供了遗传学证据，表明FUS和CHOP结构域通过反式作用来相互恢复脂肪肉瘤。这些结果确定了肿瘤相关融合基因的一种新机制，并且可能对黏液样脂肪肉瘤之外的领域产生影响。
