The arylstibonic acid compound NSC13746 disrupts B-ZIP binding to DNA in living cells

Sarah L. Heyerdahl, Julian Rozenberg, Louis Jamtgaard, Vikas Rishi, Lyuba Varticovski, Kelly Akah, Dominic Scudiero, Robert H. Shoemaker, Tatiana S. Karpova, Richard N. Day, James G. McNally, Charles Vinson

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The inhibition of DNA binding of basic leucine zipper (B-ZIP) transcription factors is a clinically relevant molecular target. Our laboratory has previously reported two methods of inhibiting B-ZIP DNA binding in solution: 1) an arylstibonic acid compound that binds to the basic region, stabilizes the B-ZIP dimer, and prevents B-ZIP DNA binding and 2) dominant negative proteins, termed A-ZIPs, that heterodimerize with B-ZIP domains in a leucine zipper-dependent manner. To determine if these two agents also inhibit DNA binding in live cells, GFP-tagged B-ZIP domains and mCherry-tagged A-ZIP domains were transfected into NIH3T3 cells to assess protein localization and Fluorescence Recovery After nuclear Photobleaching (FRAP). FRAP, showed that all six GFP-B-ZIP domains examined recovered faster in the nucleus in the presence of drug that we interpret represents an inhibition of DNA binding. Faster recovery in the presence of the A-ZIP was leucine zipper dependent. The arylstibonic also induced a cytoplasmic localization of all B-ZIP domains while the A-ZIPs induced a leucine zipper-dependent cytoplasmic localization. Thus, the change in cellular localization of B-ZIP domains could be used as a high-throughput assay for inhibitors of B-ZIP DNA binding. Additionally, the arylstibonic acid compound was cytostatic in clear cell sarcoma cells, which express a chimera between the B-ZIP domain of ATF-1 and N-terminal activation domain of EWS but not in K562 cells that express a non-B-ZIP containing chimeric protein BCR-ABL. These studies suggest that arylstibonic acid compounds or other small molecules capable of inhibiting B-ZIP DNA binding could be valuable anticancer agents.

Original languageEnglish (US)
Pages (from-to)564-573
Number of pages10
JournalEuropean Journal of Cell Biology
Volume89
Issue number7
DOIs
StatePublished - Jul 2010
Externally publishedYes

Keywords

  • Antimony
  • Arylstibonic acid
  • B-ZIP domain
  • DNA binding
  • FRAP
  • VBP

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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  • Cite this

    Heyerdahl, S. L., Rozenberg, J., Jamtgaard, L., Rishi, V., Varticovski, L., Akah, K., Scudiero, D., Shoemaker, R. H., Karpova, T. S., Day, R. N., McNally, J. G., & Vinson, C. (2010). The arylstibonic acid compound NSC13746 disrupts B-ZIP binding to DNA in living cells. European Journal of Cell Biology, 89(7), 564-573. https://doi.org/10.1016/j.ejcb.2009.11.029