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Stress-Activated Mitogen-Activated Protein Kinases c-Jun NH₂-Terminal Kinase and p38 Target Cdc25B for Degradation

¹ Division of Life Science, Graduate School of Natural Science and Technology, ² Venture Business Laboratory, Center for Innovation, and ³ Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; ⁴ Laboratory of Environmental Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan; ⁵ Division of Biochemistry, National Cancer Center Research Institute; ⁶ Division of Intractable Diseases, Research Institute, International Medical Center of Japan, Tokyo, Japan; and ⁷ Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong

Requests for reprints: Katsumi Yamashita, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Ishikawa, Japan. Phone: 81-76-264-6270; Fax: 81-76-264-6270; E-mail: katsumi{at}kenroku.kanazawa-u.ac.jp.

Key Words: Cdc25B • nongenotoxic stress • degradation • JNK • p38MAPK

Cdc25 dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Of the three mammalian Cdc25 isoforms, Cdc25A is phosphorylated by genotoxic stress–activated Chk1 or Chk2, which triggers its SCF^β-TrCP–mediated degradation. However, the roles of Cdc25B and Cdc25C in cell stress checkpoints remain inconclusive. We herein report that c-Jun NH₂-terminal kinase (JNK) induces the degradation of Cdc25B. Nongenotoxic stress induced by anisomycin caused rapid degradation of Cdc25B as well as Cdc25A. Cdc25B degradation was dependent mainly on JNK and partially on p38 mitogen-activated protein kinase (p38). Accordingly, cotransfection with JNK1, JNK2, or p38 destabilized Cdc25B. In vitro kinase assays and site-directed mutagenesis experiments revealed that the critical JNK and p38 phosphorylation site in Cdc25B was Ser¹⁰¹. Cdc25B with Ser¹⁰¹ mutated to alanine was refractory to anisomycin-induced degradation, and cells expressing such mutant Cdc25B proteins were able to override the anisomycin-induced G₂ arrest. These results highlight the importance of a novel JNK/p38-Cdc25B axis for a nongenotoxic stress–induced cell cycle checkpoint. [Cancer Res 2009;69(16):6438–44]