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Molecular Pharmacology

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Research ArticleArticle

Nuclear Factor-Y Binding to the Topoisomerase IIα Promoter Is Inhibited by Both the p53 Tumor Suppressor and Anticancer Drugs

Ashish A. Joshi, Zhong Wu, Robin F. Reed and D. Parker Suttle
Molecular Pharmacology February 2003, 63 (2) 359-367; DOI: https://doi.org/10.1124/mol.63.2.359
Ashish A. Joshi
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Zhong Wu
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Robin F. Reed
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D. Parker Suttle
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Abstract

Expression of the human DNA topoisomerase IIα (topo IIα) gene is positively regulated by the binding of the nuclear factor Y (NF-Y) transcription factor to four of five inverted CCAAT boxes (ICBs) located in its promoter. We have demonstrated previously that expression of the p53 tumor suppressor inhibits human topo IIα promoter activity in murine (10)1 cells. In this report, we demonstrate that the inhibition of topo IIα gene expression by wild-type p53 correlates with the decreased binding of the transcription factor NF-Y to the first four ICBs of the topo IIα promoter. The expression of mutant p53 does not affect the binding of NF-Y. In NIH3T3 cells, we show that topo II-targeted drugs inhibit the binding of NF-Y to ICB sites in the topo IIα promoter. This effect is seen not only with drugs that result in DNA strand breaks but also with drugs that inhibit the catalytic activity of topo II, and even with the mitotic spindle inhibitor, vinblastine. Further experiments with p53-null (10)1 cells treated with these same drugs also demonstrate decreased NF-Y binding to the topo IIα ICBs. The data presented points to the existence of both p53-dependent and -independent mechanisms for regulating NF-Y binding to ICBs in the topo IIα promoter and thus the modulation of topo IIα gene expression.

Footnotes

  • ↵1 Present address: Roquette America, Keokuk, IA.

  • ↵2 Present address: Department of Urology, University of Virginia, Charlottesville, VA.

  • This study was supported by grant CA47941 from the National Institutes of Health and a Merit Award from the Department of Veterans Affairs (to D.P.S.).

  • Abbreviations:
    topo IIα
    α isoform of DNA topoisomerase type II
    ICB
    inverted CCAAT box
    NF-Y
    nuclear factor Y
    VP-16
    etoposide
    VM-26
    teniposide
    m-AMSA
    amsacrine
    wt
    wild type
    DMEM
    Dulbecco's modified Eagle's medium
    • Received June 21, 2002.
    • Accepted November 11, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Research ArticleArticle

Nuclear Factor-Y Binding to the Topoisomerase IIα Promoter Is Inhibited by Both the p53 Tumor Suppressor and Anticancer Drugs

Ashish A. Joshi, Zhong Wu, Robin F. Reed and D. Parker Suttle
Molecular Pharmacology February 1, 2003, 63 (2) 359-367; DOI: https://doi.org/10.1124/mol.63.2.359

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Research ArticleArticle

Nuclear Factor-Y Binding to the Topoisomerase IIα Promoter Is Inhibited by Both the p53 Tumor Suppressor and Anticancer Drugs

Ashish A. Joshi, Zhong Wu, Robin F. Reed and D. Parker Suttle
Molecular Pharmacology February 1, 2003, 63 (2) 359-367; DOI: https://doi.org/10.1124/mol.63.2.359
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