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

  1. Author:
    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.

  2. Author Address

    [Heyerdahl, Sarah L.; Rozenberg, Julian; Jamtgaard, Louis; Rishi, Vikas; Akah, Kelly; Vinson, Charles] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Scudiero, Dominic] Sci Applicat Int Corp, Frederick, MD 21702 USA. [Shoemaker, Robert H.] NCI, Dev Therapeut Program, DCTD, Frederick, MD 21702 USA. [Karpova, Tatiana S.; McNally, James G.] NCI, Imaging Core Facil, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Varticovski, Lyuba] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. [Day, Richard N.] Univ Virginia, Hlth Sci Ctr, Dept Med, Charlottesville, VA 22908 USA.;Vinson, C, NCI, Metab Branch, NIH, Bldg 37,Room 3128, Bethesda, MD 20892 USA.;Vinsonc@mail.nih.gov
    1. Year: 2010
    2. Date: Jul
  2. Journal: European Journal of Cell Biology
    1. 89
    2. 7
    3. Pages: 564-573
  4. Type of Article: Article
  5. ISSN: 0171-9335
  1. 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. Published by Elsevier GmbH.

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External Sources

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  2. DOI: 10.1016/j.ejcb.2009.11.029
  3. View record in Web of Science®
  4. WOS: 000278639900008

Library Notes

  1. Fiscal Year: FY2009-2010
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