EWS/WT1 co-operates with the loss of p53 to exert its oncogenic effects and up-regulates canonical Wnt pathway signaling.
Ontology highlight
ABSTRACT: The t(11;22)(p13;q12) translocation is pathognomonic for the highly aggressive desmoplastic small round cell tumour (DSRCT). The translocation fuses exon 7 of the EWS gene to exon 8 of the WT1 gene (EWS/WT1). Two splice variants of EWS/WT1 exist, arising from the presence (+KTS) or absence (-KTS) of three amino acids: lysine, threonine and serine between zinc fingers 3 and 4. To investigate the oncogenic properties of both isoforms of EWS/WT1, we over-expressed EWS/WT1 in untransformed murine embryonic fibroblasts (MEFs). We demonstrate that neither isoform of EWS/WT1 is sufficient to transform wild type MEFs, however the oncogenic potential of both isoforms is unmasked by the loss of p53. Expression of EWS/WT1 in MEFs lacking at least one allele of p53 resulted in enhanced cell proliferation, clonogenic survival and anchorage-independent growth. In addition EWS/WT1 expression in wild type MEFs attenuated several p53-dependent responses, including cell cycle arrest after irradiation and daunorubicin induced apoptosis. We show that DSRCT commonly have copy number amplification of MDM2 and MDMX, suggesting loss of p53 function in the tumours. Expression of either isoform of EWS/WT1 in MEFs induced characteristic mRNA expression profiles, including up-regulation of canonical Wnt pathway signaling. This was validated in cell lines and in a series of DSCRT, which confirmed canonical Wnt pathway activation in the tumours. We show for the first time that both isoforms of EWS/WT1 have oncogenic potential and that in addition to co-operating with loss of p53 function can also further attenuate p53-mediated responses. In addition we provide the first link between EWS/WT1 and Wnt pathway signaling. These data provide novel insights into the function of the EWS/WT1 fusion protein which characterizes DSCRT.
ORGANISM(S): Mus musculus
PROVIDER: GSE42649 | GEO | 2014/11/01
SECONDARY ACCESSION(S): PRJNA182509
REPOSITORIES: GEO
ACCESS DATA
