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      Fat-specific FUS-DDIT3-transgenic mice establish PPARgamma inactivation is required to liposarcoma development.

      Carcinogenesis
      Adipocytes, cytology, Animals, Cell Differentiation, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 2, Fibroblasts, physiology, Humans, Liposarcoma, genetics, pathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Nude, Mice, Transgenic, PPAR gamma, antagonists & inhibitors, Promoter Regions, Genetic, RNA, isolation & purification, RNA-Binding Protein FUS, Transcription Factor CHOP, Translocation, Genetic

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          Abstract

          FUS-DDIT3 is a chimeric oncogene generated by the most common chromosomal translocation t(12;16)(q13;p11) associated to liposarcomas. The application of transgenic methods and the use of primary mesenchymal progenitor cells to the study of this sarcoma-associated FUS-DDIT3 gene fusion have provided insights into their in vivo functions and suggested mechanisms by which lineage selection may be achieved. These studies indicate that FUS-DDIT3 contributes to differentiation arrest acting at a point in the adipocyte differentiation process after induction of peroxisome proliferator-activated receptor gamma (PPARgamma) expression. To test this idea within a living mouse, we generated mice expressing FUS-DDIT3 within aP2-positive cells, because aP2 is a downstream target of PPARgamma expressed at the immature adipocyte stage. Here, we report that FUS-DDIT3 expression was successfully induced at the aP2 stage of differentiation both in vivo and in vitro. aP2-FUS-DDIT3 mice do not develop liposarcomas and exhibit an increase in white adipose tissue size. Consistent with in vivo data, mouse embryonic fibroblasts (MEFs) obtained from aP2-FUS-DDIT3 mice not only were capable of terminal differentiation but also showed an increased capacity for adipogenesis in vitro compared with wild-type MEFs. Taken together, this study provides genetic evidence that the presence of FUS-DDIT3 in an aP2-positive cell is not enough to cause liposarcoma development and establishes that PPARgamma inactivation is required for liposarcoma development.

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