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Molecular and Cellular Biology, July 2000, p. 4543-4552, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Involvement of the MKK6-p38gamma Cascade in gamma -Radiation-Induced Cell Cycle Arrestdagger

Xiaofei Wang,1 Clare H. McGowan,2 Ming Zhao,1,Dagger Liusheng He,3 Jocelyn S. Downey,1 Colleen Fearns,1 Yibin Wang,4 Shi Huang,3 and Jiahuai Han1,*

Department of Immunology1 and Department of Molecular Biology,2 The Scripps Research Institute, and Program in Oncogenes and Tumor Suppressor Genes, The Burnham Institute,3 La Jolla, California 92037, and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 212014

Received 10 November 1999/Returned for modification 22 December 1999/Accepted 3 April 2000

The p38 group of kinases belongs to the mitogen-activated protein (MAP) kinase superfamily with structural and functional characteristics distinguishable from those of the ERK, JNK (SAPK), and BMK (ERK5) kinases. Although there is a high degree of similarity among members of the p38 group in terms of structure and activation, each member appears to have a unique function. Here we show that activation of p38gamma (also known as ERK6 or SAPK3), but not the other p38 isoforms, is required for gamma -irradiation-induced G2 arrest. Activation of the MKK6-p38gamma cascade is sufficient to induce G2 arrest in cells, and expression of dominant negative alleles of MKK6 or p38gamma allows cells to escape the DNA damage-induce G2 delay. Activation of p38gamma is dependent on ATM and leads to activation of Cds1 (also known as Chk2). These data suggest a model in which activation of ATM by gamma  irradiation leads to the activation of MKK6, p38gamma , and Cds1 and that activation of both MKK6 and p38gamma is essential for the proper regulation of the G2 checkpoint in mammalian cells.

* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-8704. Fax: (858) 784-8227. E-mail: jhan{at}scripps.edu.

dagger Publication no. 12814-IMM from the Department of Immunology, The Scripps Research Institute, La Jolla, Calif.

Dagger Present address: Department of Pathology, Linkoping University, S-581 85 Linkoping, Sweden.

Molecular and Cellular Biology, July 2000, p. 4543-4552, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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