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Molecular and Cellular Biology, May 1999, p. 3551-3560, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Extracellular Signal-Regulated Kinase Activates Topoisomerase IIalpha through a Mechanism Independent of Phosphorylation

Paul S. Shapiro,1,* Anne M. Whalen,1 Nicholas S. Tolwinski,1,2 Julie Wilsbacher,3 Stacie J. Froelich-Ammon,4 Marileila Garcia,5 Neil Osheroff,6 and Natalie G. Ahn1,2

Department of Chemistry and Biochemistry,1 Howard Hughes Medical Institute,2 and SANGAMO Biosciences,4 University of Colorado, Boulder, Colorado 80309; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 752353; Cytogenetics Core Facility, University of Colorado Health Sciences Cancer Center, Denver, Colorado 802625; and Departments of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 372326

Received 19 October 1998/Returned for modification 14 December 1998/Accepted 16 February 1999

The mitogen-activated protein (MAP) kinases, extracellular signal-related kinase 1 (ERK1) and ERK2, regulate cellular responses by mediating extracellular growth signals toward cytoplasmic and nuclear targets. A potential target for ERK is topoisomerase IIalpha , which becomes highly phosphorylated during mitosis and is required for several aspects of nucleic acid metabolism, including chromosome condensation and daughter chromosome separation. In this study, we demonstrated interactions between ERK2 and topoisomerase IIalpha proteins by coimmunoprecipitation from mixtures of purified enzymes and from nuclear extracts. In vitro, diphosphorylated active ERK2 phosphorylated topoisomerase IIalpha and enhanced its specific activity by sevenfold, as measured by DNA relaxation assays, whereas unphosphorylated ERK2 had no effect. However, activation of topoisomerase II was also observed with diphosphorylated inactive mutant ERK2, suggesting a mechanism of activation that depends on the phosphorylation state of ERK2 but not on its kinase activity. Nevertheless, activation of ERK by transient transfection of constitutively active mutant MAP kinase kinase 1 (MKK1) enhanced endogenous topoisomerase II activity by fourfold. Our findings indicate that ERK regulates topoisomerase IIalpha in vitro and in vivo, suggesting a potential target for the MKK/ERK pathway in the modulation of chromatin reorganization events during mitosis and in other phases of the cell cycle.

* Corresponding author. Mailing address: Department of Chemistry and Biochemistry, Campus Box 215, University of Colorado, Boulder, CO 80309. Phone: (303) 492-7794. Fax: (303) 492-2439. E-mail: shapirop{at}stripe.colorado.edu.

Molecular and Cellular Biology, May 1999, p. 3551-3560, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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