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Ras stimulates DNA topoisomerase IIα through MEK: A link between oncogenic signaling and a therapeutic target

Oncogene volume 18, pages 7149–7160 (1999)Cite this article

Abstract

Topoisomerase IIα (topo IIα) is a major target of antitumor treatments. In an effort to determine why this protein might be a better target in tumor cells than in normal cells, we attempted to determine if the altered proliferative signaling in a tumor cell might effect the levels of expression of the topo IIα gene. In support of this idea, it was found that topo IIα was elevated following microinjection of oncogenic Ras protein. Oncogenic ras was further shown to stimulate the topo IIα promoter. Stimulation by ras was independent of the normal cell cycle regulation of this promoter. Transactivation of topo IIα by ras required both the MEK/ERK pathway, and the stress-associated protein kinase (SAPK) signaling pathway. As a direct confirmation that both ERK and SAPK were involved in topo IIα regulation, a constitutively active MEKK that stimulates these two kinases simultaneously was shown to strongly induce topo IIα promoter activity. Activation of either pathway alone, on the other hand, only slightly stimulated the topo IIα promoter. Deletion analyses showed that elements near both the 5′ and 3′ ends of the promoter were responsible for the ras stimulation. Site-directed mutagenesis further demonstrated that an Ets-like binding site near the 5′ end (−480 to −475) was one of the responsive elements. Taken together, these studies demonstrate the direct role of Ras signaling in stimulation of topo IIα expression, and thereby establish a link between the action of a common tumor mutation and the target of multiple anti-tumor reagents.

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Acknowledgements

This study was supported in part by United States Public Health Service Grants GM52271 (to DW Stacey) and CA47941 (to DP Suttle) and by a Veterans' Affairs Merit Award (to DP Suttle). The authors wish to thank Dr ID Hickson, Imperial Cancer Research Fund, University of Oxford, UK, for providing the topo IIα CAT plasmid, Dr JY Shu and S Oh for the technical assistance, and Dr M Hitomi and Dr M Golubic for their helpful discussions.

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Authors and Affiliations

  1. Department of Molecular Biology, NC2-150, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Guan Chen & Dennis W Stacey

  2. Department of Pharmacology, The University of Tennessee, Memphis, 38163, Tennessee, TN, USA

    D Parker Suttle

  3. Research Service, Veterans Affairs Medical Center, Memphis, 38104, Tennessee, TN, USA

    D Parker Suttle

  4. Institute of Pathology, Case Western Reserve University, Cleveland, 44106, Ohio, OH, USA

    Dennis Templeton

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Chen, G., Templeton, D., Suttle, D. et al. Ras stimulates DNA topoisomerase IIα through MEK: A link between oncogenic signaling and a therapeutic target. Oncogene 18, 7149–7160 (1999). https://doi.org/10.1038/sj.onc.1203149

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