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

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.

• Authors: Pedro Antonio Pérez-Mancera, Carolina Vicente-Dueñas, Inés González-Herrero, Manuel Sánchez-Martín, Teresa Flores-Corral, Isidro Sánchez-García
• Journal: Carcinogenesis (Carcinogenesis) Vol. 28 Issue 10 Pg. 2069-73 (Oct 2007) ISSN: 1460-2180 [Electronic] England
• PMID: 17468515 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DDIT3 protein, human
• PPAR gamma
• RNA-Binding Protein FUS
• Transcription Factor CHOP
• RNA

Topics

• 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 (genetics, isolation & purification)
• RNA-Binding Protein FUS (genetics)
• Transcription Factor CHOP (genetics)
• Translocation, Genetic