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Related Experiment Videos

Modification of EWS/WT1 functional properties by phosphorylation.

J Kim1, J M Lee, P E Branton

  • 1Department of Biochemistry, McGill University, McIntyre Medical Sciences Building, 3655 Drummond Street, Montreal, Quebec H3G 1Y6, Canada.

Proceedings of the National Academy of Sciences of the United States of America
|December 10, 1999
PubMed
Summary

The EWS/WT1 fusion protein, critical in desmoplastic small round cell tumors, undergoes phosphorylation that impacts its DNA binding and dimerization. This phosphorylation, particularly tyrosine modification by c-Abl, regulates the oncogenic activity of EWS/WT1.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Tumor-specific chromosomal rearrangements can generate chimeric proteins driving cancer development.
  • The EWS/WT1 fusion protein arises from a t(11;22) translocation in desmoplastic small round cell tumors.
  • This fusion protein combines the EWS amino terminus with the WT1 tumor suppressor gene's DNA binding domain.

Purpose of the Study:

  • To investigate the phosphorylation status of the EWS/WT1 fusion protein in vivo.
  • To determine how phosphorylation affects EWS/WT1's DNA binding and homodimerization.
  • To explore the interaction between EWS/WT1 and the c-Abl tyrosine kinase.

Main Methods:

  • In vivo phosphorylation analysis of EWS/WT1.
  • Assessment of EWS/WT1 DNA binding and homodimerization.

Related Experiment Videos

  • Co-immunoprecipitation assays to study EWS/WT1 and c-Abl interactions.

    • Main Results:

    • EWS/WT1 is phosphorylated on both serine and tyrosine residues in vivo.
    • Phosphorylation significantly alters EWS/WT1's DNA binding affinity and homodimerization.
    • c-Abl tyrosine kinase interacts with EWS/WT1 and negatively regulates its DNA binding via tyrosine phosphorylation.

    Conclusions:

    • The biological activity of the EWS/WT1 fusion protein is intrinsically linked to its post-translational modification state, specifically phosphorylation.
    • Tyrosine phosphorylation by c-Abl serves as a critical regulatory mechanism for EWS/WT1 function in desmoplastic small round cell tumors.
    • Understanding EWS/WT1 phosphorylation provides insights into oncogenesis and potential therapeutic targets.