Involvement of the MKK6-p38γ Cascade in γ-Radiation-Induced Cell Cycle Arrest

Abstract

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 p38γ (also known as ERK6 or SAPK3), but not the other p38 isoforms, is required for γ-irradiation-induced G₂arrest. Activation of the MKK6-p38γ cascade is sufficient to induce G₂ arrest in cells, and expression of dominant negative alleles of MKK6 or p38γ allows cells to escape the DNA damage-induce G₂ delay. Activation of p38γ 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 γ irradiation leads to the activation of MKK6, p38γ, and Cds1 and that activation of both MKK6 and p38γ is essential for the proper regulation of the G₂checkpoint in mammalian cells.

ACKNOWLEDGMENTS

We thank J. V. Kuhns for excellent secretarial assistance.

This work was supported by grants from the California Cancer Research Program (J. Han) and the PEW Scholar Program in Biomedical Science (S. Huang) and by a California Breast Cancer Research Program postdoctoral fellowship (X. Wang).

Notes

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