FUS-DDIT3 prevents the development of adipocytic precursors in liposarcoma by repressing PPARγ and C/EBPα and activating elF4E

Abstract

Background: FUS-DDIT3 is a chemeric protein generated by the most common chromosomal translocation t(12;16)(q13,p11) linked to liposarcomas, which are characterized by the accumulation of early adipocytic precursors. Current studies indicate that FUS-DDIT3 liposarcoma develops from uncommitted progenitors. However, the precise mechanism whereby FUS-DDIT3 contributes to the differentiation arrest remains to be elucidated. Methodology/Principal Findings: Here we have characterized the adipocyte regulatory protein network in liposarcomas of FUS-DITT3 transgenic mice and showed that PPARγ2 and C/EBPα expression was altered. Consistent with in vivo data, FUS-DDIT3 MEFs and human liposarcoma cell lines showed a similar downregulation of both PPARγ2 and C/ EBPα expression. Complementation studies with PPARγ2 but not C/EBPα rescued the differentiation block in committed adipocytic precursors expressing FUS-DDIT3. Our results further show that FUS-DDIT3 interferes with the control of initiation of translation by upregulation of the eutkaryotic translation initiation factors eIF2 and eIF4E both in FUS-DDIT3 mice and human liposarcomas cell lines, explaining the shift toward the trancated p30 isoform of C/EBPα in liposarcomas. Suppression of the FUS/DDIT3 transgene did rescue this adipocyte differentiation block. Morever, eIF4E was also strongly upregulated in normal adipose tissue of FUS-DDIT3 transgenic mice, suggesting that overexpression of eIF4E may be a primary event in the initiation of liposarcomas. Reporter assays showed FUS-DDIT3 is involved in the upregulation of eIF4E in liposarcomas and that both domains of the fusion protein are required for affecting eIF4E expression. Conclusions/Siginificance: Taken together, this study provides evidence of the molecular mehanisms involve in the disruption of normal adipocyte differentiation programn in liposarcoma harbouring the chimeric gene FUS-DDIT3. © 2008 Pérez-Mancera et al.