Specialized Roles of the Two Mitotic Cyclins in Somatic Cells: Cyclin A as an Activator of M Phase–promoting Factor

• DOI: 10.1091/mbc.e06-12-1092
• Publication Date: 2007-03-08T04:56:01Z
• Authors: Tsz Kan Fung; Hoi Tang Ma; Randy Y.C. Poon
• Keywords: G2 Phase; 0301 basic medicine; 571; Maturation-Promoting Factor; 610; Down-Regulation; Mitosis; Cell Cycle Proteins; Cyclin A; Cyclin B; Protein Serine-Threonine Kinases; Models, Biological; 03 medical and health sciences; Models; Proto-Oncogene Proteins; 616; CDC2 Protein Kinase; Humans; cdc25 Phosphatases; Phosphorylation; DNA Primers; Base Sequence; Nuclear Proteins; Protein-Tyrosine Kinases; Biological; Protein-Serine-Threonine Kinases; RNA Interference; HeLa Cells

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.