| Rapid cycling and precocious termination of G1 phase in cells expressing CDK1AF. | |
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MedLine Citation:
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PMID: 18480403 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In Xenopus embryos, the cell cycle is driven by an autonomous biochemical oscillator that controls the periodic activation and inactivation of cyclin B1-CDK1. The oscillator circuit includes a system of three interlinked positive and double-negative feedback loops (CDK1 -> Cdc25 -> CDK1; CDK1 -/ Wee1 -/ CDK1; and CDK1 -/ Myt1 -/ CDK1) that collectively function as a bistable trigger. Previous work established that this bistable trigger is essential for CDK1 oscillations in the early embryonic cell cycle. Here, we assess the importance of the trigger in the somatic cell cycle, where checkpoints and additional regulatory mechanisms could render it dispensable. Our approach was to express the phosphorylation site mutant CDK1AF, which short-circuits the feedback loops, in HeLa cells, and to monitor cell cycle progression by live cell fluorescence microscopy. We found that CDK1AF-expressing cells carry out a relatively normal first mitosis, but then undergo rapid cycles of cyclin B1 accumulation and destruction at intervals of 3-6 h. During these cycles, the cells enter and exit M phase-like states without carrying out cytokinesis or karyokinesis. Phenotypically similar rapid cycles were seen in Wee1 knockdown cells. These findings show that the interplay between CDK1, Wee1/Myt1, and Cdc25 is required for the establishment of G1 phase, for the normal approximately 20-h cell cycle period, and for the switch-like oscillations in cyclin B1 abundance characteristic of the somatic cell cycle. We propose that the HeLa cell cycle is built upon an unreliable negative feedback oscillator and that the normal high reliability, slow pace and switch-like character of the cycle is imposed by a bistable CDK1/Wee1/Myt1/Cdc25 system. |
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Authors:
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Joseph R Pomerening; Jeffrey A Ubersax; James E Ferrell |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-05-14 |
Journal Detail:
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Title: Molecular biology of the cell Volume: 19 ISSN: 1939-4586 ISO Abbreviation: Mol. Biol. Cell Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-07-29 Completed Date: 2008-12-22 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 9201390 Medline TA: Mol Biol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 3426-41 Citation Subset: IM |
Affiliation:
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Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals CDC2 Protein Kinase / genetics*, metabolism* Cell Cycle Cell Cycle Proteins / metabolism Cyclin B / metabolism Cyclin B1 G1 Phase* Gene Expression Regulation Gene Expression Regulation, Developmental* Hela Cells Humans Mitosis Models, Biological Mutation Nuclear Proteins / metabolism Protein-Tyrosine Kinases / metabolism Time Factors Xenopus |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM-61276/GM/NIGMS NIH HHS; R01 GM-77544/GM/NIGMS NIH HHS; R01 GM061276-07/GM/NIGMS NIH HHS; R01 GM061276-08/GM/NIGMS NIH HHS; R01 GM077544-01/GM/NIGMS NIH HHS; R01 GM077544-02/GM/NIGMS NIH HHS; R01 GM077544-03/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CCNB1 protein, human; 0/Cell Cycle Proteins; 0/Cyclin B; 0/Cyclin B1; 0/Nuclear Proteins; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.2/WEE1 protein, human; EC 2.7.11.22/CDC2 Protein Kinase |
| Comments/Corrections | |
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