βTrCP-dependent degradation of CDC25B phosphatase at the metaphase-anaphase transition is a pre-requisite for correct mitotic exit.
The dual-specificity phosphatase CDC25B, a key regulator of CDK/Cyclin complexes, is considered as the starter of mitosis. It is an unstable protein, degraded by the proteasome, but often overexpressed in various human cancers. Based on experiments carried out in Xenopus eggs, and on video microscopy studies in mammalian cells, it has been proposed that human CDC25B degradation is dependent of the F-box protein βTrCp, but the involvement of this latter protein was not formally demonstrated yet. Here, we show that indeed, in mammalian cells, βTrCp participates to CDC25B turnover, and is required for the complete degradation of CDC25B at the metaphase-anaphase transition. Using a stabilized mutant of CDC25B, which cannot interact anymore with βTrCp, we further show that, during late phases of mitosis, reduced degradation of CDC25B leads to an extended window of expression of the protein, which in turn induces a delay in mitosis exit and entails mitotic defects such as chromosomes missegregation. These findings show that a dysfunction in the rapid and precisely controlled degradation of CDC25B at the metaphase-anaphase transition is sufficient to cause genomic instability and suggest that, in human tissues, pathologic stabilization or untimed expression of CDC25B could contribute to tumorigenesis.
Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR, IFR, Universités Montpellier I and II, France.
Yann
Y
Thomas
Olivier
O
Coux
Véronique
V
Baldin
D000705:Anaphase; D000818:Animals; D045744:Cell Line, Tumor; D020090:Chromosome Segregation; D006801:Humans; D008677:Metaphase; D008938:Mitosis; D009154:Mutation; D010766:Phosphorylation; D014981:Xenopus; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
D044844:beta-Transducin Repeat-Containing Proteins; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases