O-GlcNAcylation is involved in the transcriptional activity of EWS-FLI1 in Ewing's sarcoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-01-19

AUTHORS

R Bachmaier, D N T Aryee, G Jug, M Kauer, M Kreppel, K A Lee, H Kovar

ABSTRACT

The oncogene EWS-FLI1 encodes a chimeric transcription factor expressed in Ewing's sarcoma family tumors (ESFTs). EWS-FLI1 target gene expression is thought to drive ESFT pathogenesis and, therefore, inhibition of EWS-FLI1 activity holds high therapeutic promise. As the activity of many transcription factors is regulated by post-translational modifications, we studied the presence of modifications on EWS-FLI1. The immuno-purified fusion-protein was recognized by an antibody specific for O-linked β-N-acetylglucosaminylation, and bound readily to a phosphoprotein-specific dye. Inhibition of Ser/Thr-specific phophatases increased EWS-FLI1 molecular weight and reduced its O-GlcNAc content, suggesting that phosphorylation and O-GlcNAcylation of EWS-FLI1 interact dynamically. By mutation analysis, O-GlcNAcylation was delineated to Ser/Thr residues of the amino-terminal EWS transcriptional-activation domain. Metabolic inhibition of the hexosamine biosynthetic pathway abrogated O-GlcNAcylation of EWS-FLI1 and interfered specifically with transcriptional activation of the EWS-FLI1 target Id2. These results suggest that drugs modulating glycosylation of EWS-FLI1 interfere functionally with its activity and might, therefore, constitute promising additions to the current ESFT chemotherapy. More... »

PAGES

1280-1284

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2008.484

DOI

http://dx.doi.org/10.1038/onc.2008.484

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031191918

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19151750


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