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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.
Beal,
Effect of UV on cleavage of Xenopus laevis.
1975, Pubmed,
Xenbase
Beal,
Effect of UV on cleavage of Xenopus laevis.
1975,
Pubmed
,
Xenbase Berridge,
The versatility and complexity of calcium signalling.
2001,
Pubmed Blasina,
The role of inhibitory phosphorylation of CDC2 following DNA replication block and radiation-induced damage in human cells.
1997,
Pubmed Chan,
Kinetochore structure and function.
2005,
Pubmed Chen,
Integrative analysis of cell cycle control in budding yeast.
2004,
Pubmed Ciliberto,
Steady states and oscillations in the p53/Mdm2 network.
2005,
Pubmed Cohen-Fix,
Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p.
1996,
Pubmed
,
Xenbase Cross,
Two redundant oscillatory mechanisms in the yeast cell cycle.
2003,
Pubmed Cross,
Testing a mathematical model of the yeast cell cycle.
2002,
Pubmed Elowitz,
A synthetic oscillatory network of transcriptional regulators.
2000,
Pubmed Gerhart,
Cell cycle dynamics of an M-phase-specific cytoplasmic factor in Xenopus laevis oocytes and eggs.
1984,
Pubmed
,
Xenbase Gong,
Cyclin A2 regulates nuclear-envelope breakdown and the nuclear accumulation of cyclin B1.
2007,
Pubmed Goodwin,
Oscillatory behavior in enzymatic control processes.
1965,
Pubmed Gould,
Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis.
1989,
Pubmed Gupta,
Rescue of a human cell line from endogenous Cdk1 depletion by Cdk1 lacking inhibitory phosphorylation sites.
2007,
Pubmed Hagting,
Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1.
2002,
Pubmed Harris,
The p53 pathway: positive and negative feedback loops.
2005,
Pubmed Hershko,
Components of a system that ligates cyclin to ubiquitin and their regulation by the protein kinase cdc2.
1994,
Pubmed HODGKIN,
A quantitative description of membrane current and its application to conduction and excitation in nerve.
1952,
Pubmed Jackman,
Active cyclin B1-Cdk1 first appears on centrosomes in prophase.
2003,
Pubmed Jaspersen,
Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14.
1999,
Pubmed Jin,
Role of inhibitory CDC2 phosphorylation in radiation-induced G2 arrest in human cells.
1996,
Pubmed Jin,
Nuclear localization of cyclin B1 controls mitotic entry after DNA damage.
1998,
Pubmed Jones,
Probing the precision of the mitotic clock with a live-cell fluorescent biosensor.
2004,
Pubmed Kanda,
Histone-GFP fusion protein enables sensitive analysis of chromosome dynamics in living mammalian cells.
1998,
Pubmed King,
A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B.
1995,
Pubmed
,
Xenbase King,
How proteolysis drives the cell cycle.
1996,
Pubmed Krek,
Mutations of p34cdc2 phosphorylation sites induce premature mitotic events in HeLa cells: evidence for a double block to p34cdc2 kinase activation in vertebrates.
1991,
Pubmed Leonhardt,
Dynamics of DNA replication factories in living cells.
2000,
Pubmed Lewis,
Calcium signaling mechanisms in T lymphocytes.
2001,
Pubmed Liou,
STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx.
2005,
Pubmed Listovsky,
Mammalian Cdh1/Fzr mediates its own degradation.
2004,
Pubmed
,
Xenbase Lopez-Girona,
Serine-345 is required for Rad3-dependent phosphorylation and function of checkpoint kinase Chk1 in fission yeast.
2001,
Pubmed Moir,
Nuclear lamins A and B1: different pathways of assembly during nuclear envelope formation in living cells.
2000,
Pubmed Murray,
The role of cyclin synthesis and degradation in the control of maturation promoting factor activity.
1989,
Pubmed
,
Xenbase Musacchio,
The spindle-assembly checkpoint in space and time.
2007,
Pubmed Myers,
Silencing gene expression with Dicer-generated siRNA pools.
2005,
Pubmed Nasmyth,
At the heart of the budding yeast cell cycle.
1996,
Pubmed Nigg,
Mitotic kinases as regulators of cell division and its checkpoints.
2001,
Pubmed Norbury,
Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates.
1991,
Pubmed
,
Xenbase Novak,
Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos.
1993,
Pubmed
,
Xenbase Novak,
Mathematical model of the cell division cycle of fission yeast.
2001,
Pubmed Pines,
Mitosis: a matter of getting rid of the right protein at the right time.
2006,
Pubmed Pomerening,
Systems-level dissection of the cell-cycle oscillator: bypassing positive feedback produces damped oscillations.
2005,
Pubmed
,
Xenbase Pomerening,
Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2.
2003,
Pubmed
,
Xenbase Ptacek,
Global analysis of protein phosphorylation in yeast.
2005,
Pubmed Rape,
Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry.
2004,
Pubmed Reppert,
Coordination of circadian timing in mammals.
2002,
Pubmed Rust,
Ordered phosphorylation governs oscillation of a three-protein circadian clock.
2007,
Pubmed Sarkaria,
Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
1999,
Pubmed Sha,
Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts.
2003,
Pubmed
,
Xenbase Sudakin,
The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis.
1995,
Pubmed Thron,
A model for a bistable biochemical trigger of mitosis.
1996,
Pubmed Toyoshima-Morimoto,
Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase.
2001,
Pubmed
,
Xenbase Tyson,
Regulation of the eukaryotic cell cycle: molecular antagonism, hysteresis, and irreversible transitions.
2001,
Pubmed Ubersax,
Targets of the cyclin-dependent kinase Cdk1.
2003,
Pubmed Uhlmann,
Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1.
1999,
Pubmed Visintin,
CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis.
1997,
Pubmed Waizenegger,
Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase.
2000,
Pubmed
,
Xenbase Walsh,
Phosphorylation of the cyclin b1 cytoplasmic retention sequence by mitogen-activated protein kinase and Plx.
2003,
Pubmed
,
Xenbase Wasserman,
The cyclic behavior of a cytoplasmic factor controlling nuclear membrane breakdown.
1978,
Pubmed
,
Xenbase Zhou,
Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins.
2000,
Pubmed
