Specialized roles of the two mitotic cyclins in somatic cells: cyclin A as an activator of M phase-promoting factor.
The role of cyclin B-CDC2 as M phase-promoting factor (MPF) is well established, but the precise functions of cyclin A remain a crucial outstanding issue. Here we show that down-regulation of cyclin A induces a G2 phase arrest through a checkpoint-independent inactivation of cyclin B-CDC2 by inhibitory phosphorylation. The phenotype is rescued by expressing cyclin A resistant to the RNA interference. In contrast, down-regulation of cyclin B disrupts mitosis without inactivating cyclin A-CDK, indicating that cyclin A-CDK acts upstream of cyclin B-CDC2. Even when ectopically expressed, cyclin A cannot replace cyclin B in driving mitosis, indicating the specific role of cyclin B as a component of MPF. Deregulation of WEE1, but not the PLK1-CDC25 axis, can override the arrest caused by cyclin A knockdown, suggesting that cyclin A-CDK may tip the balance of the cyclin B-CDC2 bistable system by initiating the inactivation of WEE1. These observations show that cyclin A cannot form MPF independent of cyclin B and underscore a critical role of cyclin A as a trigger for MPF activation.
Fung
Tsz Kan
TK
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Ma
Hoi Tang
HT
Poon
Randy Y C
RY
D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D016195:G2 Phase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D016200:Maturation-Promoting Factor / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D020687:cdc25 Phosphatases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D017931:DNA Primers; D016200:Maturation-Promoting Factor; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D020687:cdc25 Phosphatases; D000097869:Polo-Like Kinase 1; C499349:WEE1 protein, human; C517009:CDC25C protein, human