Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human Wilms tumor 1 WT1(-KTS) isoform time series induction in U2OS cells

ABSTRACT: The Wilms' tumor suppressor gene (WT1) encodes a zinc finger transcription factor that plays important roles during development of several organs including metanephric kidneys. A number of WT1 target genes have been identified, but the detailed mechanisms by which WT1 orchestrates renal development remain elusive. To identify WT1 target genes relevant to development, genome-wide expression profiling was performed using oligonucleotide microarrays representing 39,000 human transcripts Experiment Overall Design: Sample_source_name: UB27 cells, U2OS cells with Tetracycline-repressible WT1(-KTS) expression Experiment Overall Design: Sample_characteristics: U2OS cell line (osteosarcoma; female), Tetracycline-repressible WT1(-KTS) expression, time-course induction Experiment Overall Design: of WT1(-KTS) expression Experiment Overall Design: Sample_description: WT1(-KTS) expression was induced for 4, 8 or 12 Experiment Overall Design: hrs and the expression profile of each time-points was compared to the Experiment Overall Design: uninduced sample (0 hr).

ORGANISM(S): Homo sapiens

SUBMITTER: WeiPing Chen

PROVIDER: E-GEOD-5117 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description: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. Four independently generated pools of wild type MEFs were infected with tetracycline repressible EWS/WT1+KTS, EWS/WT1-KTS or GFP, selected with hygromycin and protein expression confirmed. Four GFP, four KTS+ and four KTS- samples were hybridized to the Ilumina BeadChip.

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Transcription profiling of human Wilms tumor 1 WT1(-KTS) isoform time series induction in U2OS cells

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