The CHFR mitotic checkpoint protein delays cell cycle progression by excluding Cyclin B1 from the nucleus.
CHFR, a novel checkpoint gene inactivated in human cancer, delays chromosome condensation in cells treated with microtubule poisons. To understand the molecular mechanism for this delay, we characterized cells with inactivated CHFR and stably transfected derivatives expressing the wild-type gene. After exposure to microtubule poisons, the CHFR-expressing cells arrested transiently in early prophase with a characteristic ruffled morphology of the nuclear envelope and no signs of chromosome condensation. Several markers suggested that Cyclin A/Cdc2 had been activated, whereas Aurora-A and -B and Cyclin B1/Cdc2 were inactive. Further, Cyclin B1 was excluded from the nucleus. Ectopic expression of Cyclin B1 with a mutant nuclear export sequence induced chromosome condensation, and thus overcame the CHFR checkpoint. We conclude that the mechanism by which CHFR delays chromosome condensation involves inhibition of accumulation of Cyclin B1 in the nucleus.
Summers
Matthew K
MK
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104-4268, USA.
Bothos
John
J
Halazonetis
Thanos D
TD
D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism*; D056744:Cyclin B1; D045325:HCT116 Cells; D006801:Humans; D008938:Mitosis; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015739:Nocodazole / Q000494:pharmacology; D000075223:Poly-ADP-Ribose Binding Proteins; D011418:Prophase / Q000187:drug effects; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D015739:Nocodazole