Cell Size Control via an Unstable Accumulating Activator and the Phenomenon of Excess Mitotic Delay

Rhind, Nick

doi:10.1002/bies.201700184

Cited by 7 publications

(5 citation statements)

References 63 publications

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“…Besides its well-established role as an M-CDK that is required for G2/M progression in primed hESCs (Neganova et al, 2014), CDK1 ablation by a specific inhibitor RO3306 caused a significant arrest at the S phase, implicating its unexpected role in facilitating S to G2/M progression in naive hESCs. The Unstable Accumulating Activator models for cellular size control propose an activator that accumulates in a size-dependent manner and triggers cell cycle progression once it has reached a certain threshold, and a strong candidate for the accumulating activator in G2 is Cdc25, the phosphatase that dephosphorylates and activates CDK1 at the G2/M transition (Rhind, 2018).…”

Section: Llmentioning

confidence: 99%

Translational and post-translational control of human naïve versus primed pluripotency

Chen¹,

Zhang²,

Wang³

et al. 2022

iScience

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Deciphering the regulatory network for human naive and primed pluripotency is of fundamental theoretical and applicable significance. Here, by combining quantitative proteomics, phosphoproteomics, and acetylproteomics analyses, we revealed RNA processing and translation as the most differentially regulated processes between naive and primed human embryonic stem cells (hESCs). Although glycolytic primed hESCs rely predominantly on the eukaryotic initiation factor 4E (eIF4E)-mediated cap-dependent pathway for protein translation, naive hESCs with reduced mammalian target of rapamycin complex (mTORC1) activity are more tolerant to eIF4E inhibition, and their bivalent metabolism allows for translating selective mRNAs via both eIF4E-dependent and eIF4E-independent/ eIF4A2-dependent pathways to form a more compact naive proteome. Globally up-regulated proteostasis and down-regulated post-translational modifications help to further refine the naive proteome that is compatible with the more rapid cycling of naive hESCs, where CDK1 plays an indispensable coordinative role. These findings may assist in better understanding the unrestricted lineage potential of naive hESCs and in further optimizing conditions for future clinical applications

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Section: Llmentioning

confidence: 99%

Translational and post-translational control of human naïve versus primed pluripotency

Chen¹,

Zhang²,

Wang³

et al. 2022

iScience

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“…Such a control implies that cells monitor their size and feed this information into the cyclin-dependent kinases (CDKs) that drive the cell cycle. However, although a range of mechanisms have been proposed as to how cell size might be monitored and fed into the CDK mitotic cell cycle control, there is no agreement as to how the molecular mechanisms operate ( Martin, 2009 ; Rhind, 2018 ; Schmoller and Skotheim, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of mutants with increased variation in cell size at onset of mitosis in fission yeast

Scotchman

Kume

Navarro

et al. 2021

Journal of Cell Science

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Fission yeast cells divide at a similar cell length with little variation about the mean. This is thought to be the result of a control mechanism that senses size and corrects for any deviations by advancing or delaying onset of mitosis. Gene deletions that advance cells into mitosis at a smaller size or delay cells entering mitosis, have identified genes potentially involved in this mechanism. However, the molecular basis of this control is still not understood. In this work, we have screened for genes, which when deleted, increase the variability in size of dividing cells. The strongest candidate of this screen was mga2. The mga2 deletion shows a greater variation in cell length at division, with a coefficient of variation (CV) of 15-24% while the wild type strain has a CV of 5-8%. Furthermore, unlike wild type cells, the mga2 deletion cells are unable to correct cell size deviations within one cell cycle. We show that the mga2 gene genetically interacts with nem1 and influences the nuclear membrane, and speculate that it may influence the nucleus/cytoplasmic transport of CDK regulators.

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“…Given the conservation of genes involved in cell cycle control from yeasts to mammalian cells ( 10 ) and that coordination of mitosis and cell division with cell size is observed across eukaryotes, the molecular mechanisms involved are likely to share commonalities. A number of models for monitoring cell size have been proposed ( 11 – 17 ), with one of the most straightforward being for changes in the concentration of a mitotic regulatory component to accompany cell size increase until a threshold level is reached that allows mitosis to proceed ( 18 ). This may be achieved either by an increase in the concentration of a mitotic activator or by a decrease in the concentration of an inhibitor ( 11 , 12 ).…”

mentioning

confidence: 99%

A quantitative and spatial analysis of cell cycle regulators during the fission yeast cycle

Curran

Dey

Rees

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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We have carried out a systems-level analysis of the spatial and temporal dynamics of cell cycle regulators in the fission yeast Schizosaccharomyces pombe . In a comprehensive single-cell analysis, we have precisely quantified the levels of 38 proteins previously identified as regulators of the G2 to mitosis transition and of 7 proteins acting at the G1- to S-phase transition. Only 2 of the 38 mitotic regulators exhibit changes in concentration at the whole-cell level: the mitotic B-type cyclin Cdc13, which accumulates continually throughout the cell cycle, and the regulatory phosphatase Cdc25, which exhibits a complex cell cycle pattern. Both proteins show similar patterns of change within the nucleus as in the whole cell but at higher concentrations. In addition, the concentrations of the major fission yeast cyclin-dependent kinase (CDK) Cdc2, the CDK regulator Suc1, and the inhibitory kinase Wee1 also increase in the nucleus, peaking at mitotic onset, but are constant in the whole cell. The significant increase in concentration with size for Cdc13 supports the view that mitotic B-type cyclin accumulation could act as a cell size sensor. We propose a two-step process for the control of mitosis. First, Cdc13 accumulates in a size-dependent manner, which drives increasing CDK activity. Second, from mid-G2, the increasing nuclear accumulation of Cdc25 and the counteracting Wee1 introduce a bistability switch that results in a rapid rise of CDK activity at the end of G2 and thus, brings about an orderly progression into mitosis.

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Cell Size Control via an Unstable Accumulating Activator and the Phenomenon of Excess Mitotic Delay

Cited by 7 publications

References 63 publications

Translational and post-translational control of human naïve versus primed pluripotency

Translational and post-translational control of human naïve versus primed pluripotency

Identification of mutants with increased variation in cell size at onset of mitosis in fission yeast

A quantitative and spatial analysis of cell cycle regulators during the fission yeast cycle

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