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Molecular and Cellular Biology, July 2001, p. 4818-4828, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4818-4828.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Cell Cycle-Regulatory CDC25A Phosphatase Inhibits Apoptosis Signal-Regulating Kinase 1

Xianghong Zou,1 Tateki Tsutsui,1,dagger Dipankar Ray,1 James F. Blomquist,2 Hidenori Ichijo,3 David S. Ucker,2 and Hiroaki Kiyokawa1,*

Departments of Molecular Genetics1 and Microbiology/Immunology,2 University of Illinois College of Medicine, Chicago, Illinois 60607, and Laboratory of Cell Signaling,3 Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Received 27 December 2000/Returned for modification 25 January 2001/Accepted 17 April 2001

CDC25A phosphatase promotes cell cycle progression by activating G1 cyclin-dependent kinases and has been postulated to be an oncogene because of its ability to cooperate with RAS to transform rodent fibroblasts. In this study, we have identified apoptosis signal-regulating kinase 1 (ASK1) as a CDC25A-interacting protein by yeast two-hybrid screening. ASK1 activates the p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal protein kinase-stress-activated protein kinase (JNK/SAPK) pathways upon various cellular stresses. Coimmunoprecipitation studies demonstrated that CDC25A physically associates with ASK1 in mammalian cells, and immunocytochemistry with confocal laser-scanning microscopy showed that these two proteins colocalize in the cytoplasm. The carboxyl terminus of CDC25A binds to a domain of ASK1 adjacent to its kinase domain and inhibits the kinase activity of ASK1, independent of and without effect on the phosphatase activity of CDC25A. This inhibitory action of CDC25A on ASK1 activity involves diminished homo-oligomerization of ASK1. Increased cellular expression of wild-type or phosphatase-inactive CDC25A from inducible transgenes suppresses oxidant-dependent activation of ASK1, p38, and JNK1 and reduces specific sensitivity to cell death triggered by oxidative stress, but not other apoptotic stimuli. Thus, increased expression of CDC25A, frequently observed in human cancers, could contribute to reduced cellular responsiveness to oxidative stress under mitogenic or oncogenic conditions, while it promotes cell cycle progression. These observations propose a mechanism of oncogenic transformation by the dual function of CDC25A on cell cycle progression and stress responses.

* Corresponding author. Mailing address: 900 S. Ashland Ave., M/C 669, Chicago, IL 60607. Phone: (312) 355-1601. Fax: (312) 413-0353. E-mail: kiyokawa{at}uic.edu.

dagger Present address: Department of Obstetrics and Gynecology, Osaka University Medical School, Osaka 565-0871, Japan.

Molecular and Cellular Biology, July 2001, p. 4818-4828, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4818-4828.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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