Mutant p53 cooperates with ETS2 to promote etoposide resistance

  1. Luis A. Martinez1,5
  1. 1Department of Biochemistry, University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA;
  2. 2Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
  3. 3University of Texas Medical Branch, Galveston, Texas 77554, USA;
  4. 4Oncology Institute, Institute of Signal Transduction, Loyola University Chicago, Maywood, Illinois 60153, USA

    Abstract

    Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5′-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially “druggable” component of mtp53's gain-of-function activity.

    Keywords

    Footnotes

    • Received October 20, 2011.
    • Accepted March 9, 2012.
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