Stress-activated mitogen-activated protein kinases c-Jun NH2-terminal kinase and p38 target Cdc25B for degradation.
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 SCFbeta-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.
Uchida
Sanae
S
Division of Life Science, Graduate School of Natural Science and Technology, Venture Business Laboratory, Center for Innovation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Yoshioka
Katsuji
K
Kizu
Ryoichi
R
Nakagama
Hitoshi
H
Matsunaga
Tsukasa
T
Ishizaka
Yukihito
Y
Poon
Randy Y C
RY
Yamashita
Katsumi
K
D000841:Anisomycin / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D050505:Mutant Proteins; D011500:Protein Synthesis Inhibitors; D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases; D006918:Hydroxyurea