Pro-apoptotic role of Cdc25A: activation of cyclin B1/Cdc2 by the Cdc25A C-terminal domain.
Cdc25A is a dual specificity protein phosphatase that activates cyclin/cyclin-dependent protein kinase (Cdk) complexes by removing inhibitory phosphates from conserved threonine and tyrosine in Cdks. To address how Cdc25A promotes apoptosis, Jurkat cells were treated with staurosporine, an apoptosis inducer. Upon staurosporine treatment, a Cdc25A C-terminal 37-kDa fragment, designated C37, was generated by caspase cleavage at Asp-223. Thr-507 in C37 became dephosphorylated, which prevented 14-3-3 binding, as shown previously. C37 exhibited higher phosphatase activity than full-length Cdc25A. C37 with alanine substitution for Thr-507 (C37/T507A) that imitated the cleavage product during staurosporine treatment interacted with Cdc2, Cdk2, cyclin A, and cyclin B1 and markedly activated cyclin B1/Cdc2. The dephosphorylation of Thr-507 might expose the Cdc2/Cdk2-docking site in C37. C37/T507A also induced apoptosis in Jurkat and K562 cells, resulting from activating cyclin B1/Cdc2 but not Cdk2. Thus, this study reveals that Cdc25A is a pro-apoptotic protein that amplifies staurosporine-induced apoptosis through the activation of cyclin B1/Cdc2 by its C-terminal domain.
Chou
Sung-Tau
ST
National Institute of Cancer Research, National Health Research Institutes, Number 35, Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan.
Yen
Yi-Chen
YC
Lee
Chin-Mei
CM
Chen
Mei-Shya
MS
D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry; D020687:cdc25 Phosphatases / Q000378:metabolism*
D056744:Cyclin B1; D034741:RNA, Small Interfering; D025801:Ubiquitin; D005982:Glutathione Transferase; D016203:CDC2 Protein Kinase; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D020169:Caspases; D046988:Proteasome Endopeptidase Complex