Core Control Principles of the Eukaryotic Cell Cycle

Basu, Souradeep; Nurse, Paul; Jones, Andrew W.

doi:10.21203/rs.3.rs-1008929/v1

Cited by 5 publications

(5 citation statements)

References 25 publications

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“…We conclude that this level of cyclin is sufficient to generate enough CDK activity to undergo mitosis but is restrained by the Cdc25/Wee1 regulatory loop until late in G2. The difference in Cdc13 concentration from mid-G2 to mitotic onset is about one-third, which could correspond to a "CDK buffer zone," where cells undergo mitosis with a higher level of CDK activity than is strictly necessary for the completion of mitosis (17,49).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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.

Self Cite

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“…Notably, CDKN2A-CDK4/CDK6/CCND1 axis was affected recurrently: CDKN2A silencing was found in 35% of GC patients, CDK6 amplification was observed in 9% of GC patients and CCND1 amplification in 7% [9,10]. These alterations accelerate tumor cell transition from G1 to S phase and result in uncontrolled cell proliferation [11][12][13][14]. Three CDK4/6 inhibitors (abemaciclib, ABE; ribociclib, RIB; palbociclib, PAL) have been approved for the treatment of hormone-receptor-positive, HER2-negative, advanced breast cancer and more CDK4/6 inhibitors have entered clinical trials for the treatment of various cancer types [15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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Background Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors. Methods Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models. Results We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models. Conclusion This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.

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“…cyclin B1) in G2. Although, recent evidence suggests that the cyclins are redundant in respect of cell cycle progression (rise and fall of any single cyclin type or any combination of cyclins would achieve progression) [34]. In quiescent cells Ras activity causes production of G1 cyclins to start this process.…”

Section: Discussionmentioning

confidence: 99%

Wild-type N-Ras Complements Mutant K-Ras in Pancreatic Cancer Cell Lines but K-Ras has a Specific Role in Cell Cycle Independent Regulation of G2 Cyclins

Ferguson¹

2022

Preprint

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Development of K-Ras independence may explain failure of targeted therapy for pancreatic cancer (PC). In this paper active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. Knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism but only K-Ras depletion caused a decrease in G2 cyclins, proteasome inhibition reversed this and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from G2 phase to slow relative to completion of S-phase, suggesting mutant K-Ras may inhibit APC/c prior to anaphase but stabilizes G2 cyclins independently of this. We propose that during tumorigenesis, cancer cells expressing wild type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of cell cycle independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division even in cells where K-Ras is inhibited. Keywords: Pancreatic Ductal Adenocarcinoma, K-Ras, N-Ras, G2 cyclins.

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Core Control Principles of the Eukaryotic Cell Cycle

Cited by 5 publications

References 25 publications

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

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

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Wild-type N-Ras Complements Mutant K-Ras in Pancreatic Cancer Cell Lines but K-Ras has a Specific Role in Cell Cycle Independent Regulation of G2 Cyclins

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