Analysis of the mitotic exit control system using locked levels of stable mitotic cyclin.

Molecular Systems Biology
Benjamin J DrapkinFrederick R Cross

Abstract

Cyclin-dependent kinase (Cdk) both promotes mitotic entry (spindle assembly and anaphase) and inhibits mitotic exit (spindle disassembly and cytokinesis), leading to an elegant quantitative hypothesis that a single cyclin oscillation can function as a ratchet to order these events. This ratchet is at the core of a published ODE model for the yeast cell cycle. However, the ratchet model requires appropriate cyclin dose-response thresholds. Here, we test the inhibition of mitotic exit in budding yeast using graded levels of stable mitotic cyclin (Clb2). In opposition to the ratchet model, stable levels of Clb2 introduced dose-dependent delays, rather than hard thresholds, that varied by mitotic exit event. The ensuing cell cycle was highly abnormal, suggesting a novel reason for cyclin degradation. Cdc14 phosphatase antagonizes Clb2-Cdk, and Cdc14 is released from inhibitory nucleolar sequestration independently of stable Clb2. Thus, Cdc14/Clb2 balance may be the appropriate variable for mitotic regulation. Although our results are inconsistent with the aforementioned ODE model, revision of the model to allow Cdc14/Clb2 balance to control mitotic exit corrects these discrepancies, providing theoretical support for our conclusions.

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Citations

Jan 22, 2010·Molecular Biology of the Cell·Jonathan A Robbins, Frederick R Cross
Dec 2, 2011·Molecular Biology of the Cell·Qing Kang, Joseph R Pomerening
Feb 4, 2011·Journal of the Royal Society, Interface·P K VinodBela Novak
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Jun 23, 2011·PloS One·Catherine Oikonomou, Frederick R Cross
Sep 4, 2013·The Journal of Cell Biology·Claudio VernieriAndrea Ciliberto
Feb 19, 2011·Mathematical Biosciences·Baldiri SalvadoRui Alves
Sep 21, 2010·Current Opinion in Genetics & Development·Catherine Oikonomou, Frederick R Cross
Feb 19, 2015·The Plant Journal : for Cell and Molecular Biology·Frederick R Cross, James G Umen
Jul 26, 2011·Fungal Genetics and Biology : FG & B·Yao-Wei TzengYue-Li Juang
Jan 8, 2016·PLoS Computational Biology·Daniel D Seaton, J Krishnan
Jul 1, 2017·Journal of Cell Science·Brendan L Powers, Mark C Hall
Apr 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Silvia TognettiFrancesc Posas
Aug 29, 2017·Nature Methods·Sahand Jamal RahiFrederick R Cross
Jun 13, 2021·NPJ Systems Biology and Applications·Matteo Barberis

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Methods Mentioned

BETA
biosensor

Software Mentioned

MatLab
MultiGauge

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