Pérez-Losada J, Pintado B, Gutiérrez-Adán A, Flores T, Bañares-González B, del Campo J C, Martín-Martín J F, Battaner E, Sánchez-García I
Departamento de Proliferación y Diferenciacion Celular, Instituto de Microbiología Bioquímica, CSIC/Universidad de Salamanca, Edificio Departamental, Avda del Campo Charro s/n, 37007-Salamanca, Spain.
Oncogene. 2000 May 11;19(20):2413-22. doi: 10.1038/sj.onc.1203572.
The characteristic t(12;16)(q13;p11) chromosomal translocation, which leads to gene fusion that encodes the FUS-CHOP chimeric protein, is associated with human liposarcomas. The altered expression of FUS-CHOP has been implicated in a characteristic subgroup of human liposarcomas. We have introduced the FUS-CHOP transgene into the mouse genome in which the expression of the transgene is successfully driven by the elongation factor 1alpha (EF1alpha) promoter to all tissues. The consequent overexpression of FUS-CHOP results in most of the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation of intracellular lipid, induction of adipocyte-specific genes and a concordant block in the differentiation program. We have demonstrated that liposarcomas in the FUS-CHOP transgenic mice express high levels of the adipocyte regulatory protein PPARgamma, whereas it is not expressed in embryonic fibroblasts from these animals following induction to differentiation toward the adipocyte lineage, indicating that the in vitro system does not really reflect the in vivo situation and the developmental defect is downstream of PPARgamma expression. No tumors of other tissues were found in these transgenic mice despite widespread activity of the EF1alpha promoter. This establishes FUS-CHOP overexpression as a key determinant of human liposarcomas and provide the first in vivo evidence for a link between a fusion gene created by a chromosomal translocation and a solid tumor.
特征性的t(12;16)(q13;p11)染色体易位会导致编码FUS-CHOP嵌合蛋白的基因融合，这与人类脂肪肉瘤相关。FUS-CHOP的表达改变与人类脂肪肉瘤的一个特征性子集有关。我们已将FUS-CHOP转基因导入小鼠基因组，其中转基因的表达由伸长因子1α(EF1α)启动子成功驱动至所有组织。FUS-CHOP的过度表达导致了人类脂肪肉瘤的大多数症状，包括出现圆形核的脂肪母细胞、细胞内脂质积累、脂肪细胞特异性基因的诱导以及分化程序中的一致阻滞。我们已证明，FUS-CHOP转基因小鼠中的脂肪肉瘤表达高水平的脂肪细胞调节蛋白PPARγ，而在诱导这些动物的胚胎成纤维细胞向脂肪细胞谱系分化后，该蛋白在其中不表达，这表明体外系统并不能真正反映体内情况，且发育缺陷在PPARγ表达的下游。尽管EF1α启动子广泛活跃，但在这些转基因小鼠中未发现其他组织的肿瘤。这确立了FUS-CHOP的过度表达是人类脂肪肉瘤的关键决定因素，并为染色体易位产生的融合基因与实体瘤之间的联系提供了首个体内证据。
