Chfr acts with the p38 stress kinases to block entry to mitosis in mammalian cells.
Entry into mitosis in vertebrate cells is guarded by a checkpoint that can be activated by a variety of insults, including chromosomal damage and disrupting microtubules. This checkpoint acts at the end of interphase to delay cells from entering mitosis, causing cells in prophase to decondense their chromosomes and return to G2 phase. Here, we show that in response to microtubule poisons this "antephase" checkpoint is primarily mediated by the p38 stress kinases and requires the Chfr protein that is absent or inactive in several transformed cell lines and lung tumors. Furthermore, in contrast to previous reports, we find that the checkpoint requires ubiquitylation but not proteasome activity, which is in agreement with the recent demonstration that Chfr conjugates ubiquitin through lysine 63 and not lysine 48.
Wellcome/Cancer Research UK Gurdon Institute, and Department of Zoology, Tennis Court Rd., University of Cambridge, Cambridge CB2 1QR, England, UK.
Takahiro
T
Matsusaka
Jonathon
J
Pines
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002875:Chromosomes / Q000648:ultrastructure; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016195:G2 Phase; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008870:Microtubules / Q000648:ultrastructure; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D008938:Mitosis; D009097:Multienzyme Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D011418:Prophase; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D019925:Cyclin A; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D025801:Ubiquitin; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine