Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase

Dmitry V. Bulavin, Yuichiro Higashimoto, Ian J. Popoff, William A. Gaarde, Venkatesha Basrur, Olga Potapova, Ettore Appella and Albert J. Fornace ()
Additional contact information
Dmitry V. Bulavin: Division of Basic Science and
Yuichiro Higashimoto: National Cancer Institute, National Institutes of Health
Ian J. Popoff: Isis Pharmaceuticals Inc.
William A. Gaarde: Isis Pharmaceuticals Inc.
Venkatesha Basrur: National Cancer Institute, National Institutes of Health
Olga Potapova: Laboratory of Biological Chemistry, National Institute on Aging, NIH
Ettore Appella: National Cancer Institute, National Institutes of Health
Albert J. Fornace: Division of Basic Science and

Nature, 2001, vol. 411, issue 6833, 102-107

Abstract: Abstract Response to genotoxic stress can be considered as a multistage process involving initiation of cell-cycle arrest and maintenance of arrest during DNA repair1. Although maintenance of G2/M checkpoints is known to involve Chk1, Chk2/Rad53 and upstream components, the mechanisms involved in its initiation are less well defined1,2,3,4. Here we report that p38 kinase has a critical role in the initiation of a G2 delay after ultraviolet radiation. Inhibition of p38 blocks the rapid initiation of this checkpoint in both human and murine cells after ultraviolet radiation. In vitro, p38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. In vivo, inhibition of p38 prevents both phosphorylation of Cdc25B at serine 309 and 14-3-3 binding after ultraviolet radiation, and mutation of this site is sufficient to inhibit the checkpoint initiation. In contrast, in vivo Cdc25C binding to 14-3-3 is not affected by p38 inhibition after ultraviolet radiation. We propose that regulation of Cdc25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation.

Date: 2001
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DOI: 10.1038/35075107

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