Abstract
BackgroundFUS-DDIT3 is a chimeric 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 FindingsHere 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 PPARγ 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 eukaryotic translation initiation factors eIF2 and eIF4E both in FUS-DDIT3 mice and human liposarcomas cell lines, explaining the shift towards the truncated p30 isoform of C/EBPα in liposarcomas. Suppression of the FUS-DDIT3 transgene did rescue this adipocyte differentiation block. Moreover, 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/SignificanceTaken together, this study provides evidence of the molecular mechanisms involve in the disruption of normal adipocyte differentiation program in liposarcoma harbouring the chimeric gene FUS-DDIT3.
Highlights
Myxoid/round cell liposarcoma is the most common subtype of liposarcoma, accounting for about 40% of all cases [1,2]
The fact that FUS-DDIT3–associated liposarcomas initiate in uncommitted progenitor cells and generate early adipocytic precursors indicate an important role for FUS-DDIT3 in the control of early adipocytic development
To explore the molecular basis through which FUS-DDIT3 impairs the normal adipocyte differentiation program, we examined the expression levels of the proteins responsible for normal adipogenesis in liposarcomas arisen in FUS-DDIT3 transgenic mice [17]
Summary
Myxoid/round cell liposarcoma is the most common subtype of liposarcoma, accounting for about 40% of all cases [1,2]. The tumor cells are characterized by the chromosomal translocation t(12;16)(q13;p11), which produces the FUS-DDIT3 oncogene [3,4,5]. This oncogene consists of the NH2-terminal domain of FUS (previously termed translocated in liposarcoma, TLS) fused to the entire codifying sequence of DDIT3 (previously termed CHOP) [4,5]. FUS-DDIT3 has not been found in tumor types other than myxoid/round cell liposarcoma [3,4,5]. FUS-DDIT3 is a chimeric 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. The precise mechanism whereby FUSDDIT3 contributes to the differentiation arrest remains to be elucidated
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