A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP.

Abstract

In human myxoid liposaicoma, a chromosomal rearrangement leads to fusion of the growth-arresting and DNA-damage-inducible transcription factor CHOP (GADD153) to a peptide fragment encoded by the TLS gene. We have found that wild-type TLS and a closely related sarcoma-associated protein, EWS, are both abundant nuclear proteins that associate in vivo with products of RNA polymerase II transcription. This association leads to the formation of a ternary complex with other heterogeneous RNA-binding proteins (

The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

“…The importance of the FUS N-terminal part for oncogenic activity of FUS-DDIT3 was further confirmed by NIH-3T3-based transformation assays (Zinszner et al, 1994) and in transgenic mice (Perez-Losada et al, 2000b).…”

“…The contribution of FUS, EWSR1 and TAF15 to the oncogenic activity of fusion oncogenes is well documented (Kovar et al, 1994;Zinszner et al, 1994Zinszner et al, , 1997Perez-Losada et al, 2000a). The three genes may replace each other as fusion partners with specific transcription factors, indicating that the N-terminal parts of the three proteins share important functions.…”

“…All three genes form fusion oncogenes, generated by chromosome translocations in a large group of human sarcomas and leukemias (Perez-Losada et al, 2000b;Kovar, 2005). The fusion proteins consist of N-terminal parts of FUS, EWS or TAF15, which are juxtaposed to the DNA-binding parts of various transcription factors, and the chimeric proteins have been shown to act as abnormal transcription factors (Ohno et al, 1993;Sanchez Garcia and Rabbitts, 1994;Zinszner et al, 1994). In some tumor types, FUS, EWSR1 and TAF15 replace each other as 5 0 fusion partners showing that the N-terminal parts of their protein products share features and functions important for cell transformation and tumor development in these groups of sarcomas and leukemias.…”

Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

“…We find here that the CoAA activation domain is highly homologous to the Nterminal oncogenic domains of EWS family oncoproteins. The oncogenic domains of EWS fusion proteins are essential for tumorigenesis (Zinszner et al, 1994;Sorensen and Triche, 1996;Kim and Pelletier, 1999) and deregulate cell differentiation through altered alternative splicing (Yang et al, 2000). As aberrant alternative splicing is an intrinsic property for cancer cells (Kalnina et al, 2005), this phenomenon suggests that CoAA and EWS might have overlapping splicing functions in tumorigenesis.…”

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II

“…The EWS-Fli1 fusion gene codes for a chimeric protein in which the amino terminal moiety of EWS, which is rich in glutamine, serine and tyrosine residues, is fused to the carboxy-terminal DNA-binding domain (ets domain) of Fli1 (Delattre et al, 1992). EWS was the ®rst member of a growing family of RNA-binding proteins, including TLS/FUS (Zinszner et al, 1994;Rabbitts et al, 1993;Crozat et al, 1993), hTAF II 68 (Bertolotti et al, 1996), the snRNP associated 69 KD protein (Hackl and Luhrmann, 1996), the bovine Pigpen protein (Alliegro and Alliegro, 1996) and Drosophila Cabeza/SARFH (Stolow and Haynes, 1995;Immanuel et al, 1995), that share distinct structural characteristics in their carboxy termini, such as an RNP motif, RGG boxes and a putative zinc-®nger domain. However, its biological functions largely remain elusive.…”