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Cells
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The Regulation of the Cell Cycle
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The Regulation of the Cell Cycle

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Proliferation and Division".

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 30134

Special Issue Editors

Prof. Dr. Rustem E. Uzbekov

E-Mail Website
Guest Editor
Laboratory of Cell Biology and Electron Microscopy, Faculty of Medicine, University of Tours, 10, Boulevard Tonnelle, 37032 Tours, France
Interests: centrosome; centriole; cilia; flagella; cytoskeleton; mitosis; cell cycle
Special Issues, Collections and Topics in MDPI journals
Dr. Claude Prigent

E-Mail Website
Guest Editor
Directeur Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), Cell Cycle Team, CNRS CRBM UMR5237, CEDEX 05, 34293 Montpellier, France
Interests: mitosis; spindle; centrosome; kinase; microtubule; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The cell cycle was first divided into two stages: interphase and mitosis. Mitosis quickly attracted attention as the cell was undergoing very dramatic changes that were easily observed under a simple microscope. During the interphase, no change was observed except for the doubling of the cell size. It was only by using labeled nucleotides that they were noticed to be incorporated into DNA for a period defined as the S phase (DNA synthesis). Between the S phase and mitosis were then defined the G1 and G2 phases (for gap). Phase G1 is a preparation phase for phase S, and phase G2 is the phase preparing for mitosis. We must not forget that, historically, the cell cycle is the DNA cycle. Once these stages were defined in time, the cell cycle has been the subject of intense research: notably, to determine what was the molecular basis of cell cycle control. The 2001 Nobel Prize in Physiology or Medicine awarded to Sir Paul Nurse, Sir Tim Hunt and Dr. Lee Hartwell recognized the discovery of the two fundamental principles of cell cycle progression. First of all, “the motors of the cell cycle” which ensure the progression of the cycle corresponding to a combination of two proteins: a protein kinase and a cyclin protein (cdk/cyclin). There are currently several cdks and several cyclins allowing many cdk/cyclin combinations. Second, the "quality control" aspects, which ensure that the cycle progresses without errors, correspond to very complex mechanisms that strictly check every event before allowing the cell cycle to progress to the next stage. In a spectacular way, the mechanisms of cell cycle control have been preserved during evolution, first revealing the importance of these controls for the division of eukaryotic cells but also allowing their study in unicellular organisms, which easy to manipulate for extrapolations to multicellular organisms and further up to humans and pathologies linked to the cycle. The current challenges now seem to lie in our comprehension of the division of the variety of different cells in complex multicellular organisms like humans: How do stem cells divide? How do cells divide in an epithelium to preserve the barrier? How is the division of cells controlled to maintain organ size? How does a cell escape cell cycle controls to become cancerous?

This Special Issue of the Journal Cells aims to familiarize readers with the diverse aspects of cell cycle, its history and principles. It will collect answers from leading cell cycle specialists to the most pressing issues related to its current investigation in multicellular organisms and its link to human pathologies in particular cancers.

These questions we seek to answer include, but are not limited to, the following:

(1) What controls the cell cycle?

(2) Why so many cdk/cyclin?

(3) What is a checkpoint?

(4) What is the link between Go and cilia?

(5) What is G1 for?

(6) What are S phase and DNA replication and what link is there between them?

(7) What is the link between S phase and centrosome duplication?

(8) What is G2 for?

(9) What is mitosis?

(10) What is cytokinesis?

(11) What is the link between cell cycle and evolution?

(12) What is the cell cycle of stem cells, and “asymmetric division”?

(13) What is cell division in an epithelium?

(14) What is the link between cell cycle and cancers?

(15) What is the link between cell cycle and organ size?

Prof. Rustem E. Uzbekov
Dr. Claude Prigent
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cell cycle
  • interphase
  • mitosis
  • cdk/cyclin
  • checkpoint
  • S-phase
  • DNA replication
  • centrosome duplication
  • cytokinesis

Published Papers (7 papers)

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Research

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19 pages, 4099 KiB  
Article
Modulation of Cell-Cycle Progression by Hydrogen Peroxide-Mediated Cross-Linking and Degradation of Cell-Adhesive Hydrogels
by Wildan Mubarok, Kelum Chamara Manoj Lakmal Elvitigala, Masaki Nakahata, Masaru Kojima and Shinji Sakai
Cells 2022, 11(5), 881; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050881 - 03 Mar 2022
Cited by 12 | Viewed by 3129
Abstract
The cell cycle is known to be regulated by features such as the mechanical properties of the surrounding environment and interaction of cells with the adhering substrates. Here, we investigated the possibility of regulating cell-cycle progression of the cells on gelatin/hyaluronic acid composite [...] Read more.
The cell cycle is known to be regulated by features such as the mechanical properties of the surrounding environment and interaction of cells with the adhering substrates. Here, we investigated the possibility of regulating cell-cycle progression of the cells on gelatin/hyaluronic acid composite hydrogels obtained through hydrogen peroxide (H2O2)-mediated cross-linking and degradation of the polymers by varying the exposure time to H2O2 contained in the air. The stiffness of the hydrogel varied with the exposure time. Human cervical cancer cells (HeLa) and mouse mammary gland epithelial cells (NMuMG) expressing cell-cycle reporter Fucci2 showed the exposure-time-dependent different cell-cycle progressions on the hydrogels. Although HeLa/Fucci2 cells cultured on the soft hydrogel (Young’s modulus: 0.20 and 0.40 kPa) obtained through 15 min and 120 min of the H2O2 exposure showed a G2/M-phase arrest, NMuMG cells showed a G1-phase arrest. Additionally, the cell-cycle progression of NMuMG cells was not only governed by the hydrogel stiffness, but also by the low-molecular-weight HA resulting from H2O2-mediated degradation. These results indicate that H2O2-mediated cross-linking and degradation of gelatin/hyaluronic acid composite hydrogel could be used to control the cell adhesion and cell-cycle progression. Full article
(This article belongs to the Special Issue The Regulation of the Cell Cycle)
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17 pages, 3338 KiB  
Article
Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines
by I-Lun Hsin, Huang-Pin Shen, Hui-Yi Chang, Jiunn-Liang Ko and Po-Hui Wang
Cells 2021, 10(11), 2916; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112916 - 27 Oct 2021
Cited by 15 | Viewed by 4437
Abstract
Gene mutations in PIK3CA, PIK3R1, KRAS, PTEN, and PPP2R1A commonly detected in type I endometrial cancer lead to PI3K/Akt/mTOR pathway activation. Bimiralisib (PQR309), an orally bioavailable selective dual inhibitor of PI3K and mTOR, has been studied in preclinical models and clinical trials. The [...] Read more.
Gene mutations in PIK3CA, PIK3R1, KRAS, PTEN, and PPP2R1A commonly detected in type I endometrial cancer lead to PI3K/Akt/mTOR pathway activation. Bimiralisib (PQR309), an orally bioavailable selective dual inhibitor of PI3K and mTOR, has been studied in preclinical models and clinical trials. The aim of this study is to evaluate the anticancer effect of PQR309 on endometrial cancer cells. PQR309 decreased cell viability in two-dimensional and three-dimensional cell culture models. PQR309 induced G1 cell cycle arrest and little cell death in endometrial cancer cell lines. It decreased CDK6 expression and increased p27 expression. Using the Proteome Profiler Human XL Oncology Array and Western blot assay, the dual inhibitor could inhibit the expressions of c-Myc and mtp53. KJ-Pyr-9, a c-Myc inhibitor, was used to prove the role of c-Myc in endometrial cancer survival and regulating the expression of mtp53. Knockdown of mtp53 lowered cell proliferation, Akt/mTOR pathway activity, and the expressions of c-Myc. mtp53 silence enhanced PQR309-inhibited cell viability, spheroid formation, and the expressions of p-Akt, c-Myc, and CDK6. This is the first study to reveal the novel finding of the PI3K/mTOR dual inhibitor in lowering cell viability by abolishing the PI3K/Akt/mTOR/c-Myc/mtp53 positive feedback loop in endometrial cancer cell lines. Full article
(This article belongs to the Special Issue The Regulation of the Cell Cycle)
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22 pages, 63851 KiB  
Article
Mitotic Acetylation of Microtubules Promotes Centrosomal PLK1 Recruitment and Is Required to Maintain Bipolar Spindle Homeostasis
by Sylvia Fenosoa Rasamizafy, Claude Delsert, Gabriel Rabeharivelo, Julien Cau, Nathalie Morin and Juliette van Dijk
Cells 2021, 10(8), 1859; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081859 - 22 Jul 2021
Cited by 5 | Viewed by 2802
Abstract
Tubulin post-translational modifications regulate microtubule properties and functions. Mitotic spindle microtubules are highly modified. While tubulin detyrosination promotes proper mitotic progression by recruiting specific microtubule-associated proteins motors, tubulin acetylation that occurs on specific microtubule subsets during mitosis is less well understood. Here, we [...] Read more.
Tubulin post-translational modifications regulate microtubule properties and functions. Mitotic spindle microtubules are highly modified. While tubulin detyrosination promotes proper mitotic progression by recruiting specific microtubule-associated proteins motors, tubulin acetylation that occurs on specific microtubule subsets during mitosis is less well understood. Here, we show that siRNA-mediated depletion of the tubulin acetyltransferase ATAT1 in epithelial cells leads to a prolonged prometaphase arrest and the formation of monopolar spindles. This results from collapse of bipolar spindles, as previously described in cells deficient for the mitotic kinase PLK1. ATAT1-depleted mitotic cells have defective recruitment of PLK1 to centrosomes, defects in centrosome maturation and thus microtubule nucleation, as well as labile microtubule-kinetochore attachments. Spindle bipolarity could be restored, in the absence of ATAT1, by stabilizing microtubule plus-ends or by increasing PLK1 activity at centrosomes, demonstrating that the phenotype is not just a consequence of lack of K-fiber stability. We propose that microtubule acetylation of K-fibers is required for a recently evidenced cross talk between centrosomes and kinetochores. Full article
(This article belongs to the Special Issue The Regulation of the Cell Cycle)
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Review

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15 pages, 2690 KiB  
Review
Duplication and Segregation of Centrosomes during Cell Division
by Claude Prigent and Rustem Uzbekov
Cells 2022, 11(15), 2445; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152445 - 07 Aug 2022
Cited by 8 | Viewed by 5258
Abstract
During its division the cell must ensure the equal distribution of its genetic material in the two newly created cells, but it must also distribute organelles such as the Golgi apparatus, the mitochondria and the centrosome. DNA, the carrier of heredity, located in [...] Read more.
During its division the cell must ensure the equal distribution of its genetic material in the two newly created cells, but it must also distribute organelles such as the Golgi apparatus, the mitochondria and the centrosome. DNA, the carrier of heredity, located in the nucleus of the cell, has made it possible to define the main principles that regulate the progression of the cell cycle. The cell cycle, which includes interphase and mitosis, is essentially a nuclear cycle, or a DNA cycle, since the interphase stages names (G1, S, G2) phases are based on processes that occur exclusively with DNA. However, centrosome duplication and segregation are two equally important events for the two new cells that must inherit a single centrosome. The centrosome, long considered the center of the cell, is made up of two small cylinders, the centrioles, made up of microtubules modified to acquire a very high stability. It is the main nucleation center of microtubules in the cell. Apart from a few exceptions, each cell in G1 phase has only one centrosome, consisting in of two centrioles and pericentriolar materials (PCM), which must be duplicated before the cell divides so that the two new cells formed inherit a single centrosome. The centriole is also the origin of the primary cilia, motile cilia and flagella of some cells. Full article
(This article belongs to the Special Issue The Regulation of the Cell Cycle)
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12 pages, 970 KiB  
Review
A Mechanistic Model for Cell Cycle Control in Which CDKs Act as Switches of Disordered Protein Phase Separation
by Liliana Krasinska and Daniel Fisher
Cells 2022, 11(14), 2189; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11142189 - 13 Jul 2022
Cited by 3 | Viewed by 2169
Abstract
Cyclin-dependent kinases (CDKs) are presumed to control the cell cycle by phosphorylating a large number of proteins involved in S-phase and mitosis, two mechanistically disparate biological processes. While the traditional qualitative model of CDK-mediated cell cycle control relies on differences in inherent substrate [...] Read more.
Cyclin-dependent kinases (CDKs) are presumed to control the cell cycle by phosphorylating a large number of proteins involved in S-phase and mitosis, two mechanistically disparate biological processes. While the traditional qualitative model of CDK-mediated cell cycle control relies on differences in inherent substrate specificity between distinct CDK-cyclin complexes, they are largely dispensable according to the opposing quantitative model, which states that changes in the overall CDK activity level promote orderly progression through S-phase and mitosis. However, a mechanistic explanation for how such an activity can simultaneously regulate many distinct proteins is lacking. New evidence suggests that the CDK-dependent phosphorylation of ostensibly very diverse proteins might be achieved due to underlying similarity of phosphorylation sites and of the biochemical effects of their phosphorylation: they are preferentially located within intrinsically disordered regions of proteins that are components of membraneless organelles, and they regulate phase separation. Here, we review this evidence and suggest a mechanism for how a single enzyme’s activity can generate the dynamics required to remodel the cell at mitosis. Full article
(This article belongs to the Special Issue The Regulation of the Cell Cycle)
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14 pages, 1345 KiB  
Review
Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models
by Daniel Fisher and Liliana Krasinska
Cells 2022, 11(13), 2019; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132019 - 24 Jun 2022
Cited by 4 | Viewed by 4703
Abstract
In eukaryotes, cyclin-dependent kinases (CDKs) are required for the onset of DNA replication and mitosis, and distinct CDK–cyclin complexes are activated sequentially throughout the cell cycle. It is widely thought that specific complexes are required to traverse a point of commitment to the [...] Read more.
In eukaryotes, cyclin-dependent kinases (CDKs) are required for the onset of DNA replication and mitosis, and distinct CDK–cyclin complexes are activated sequentially throughout the cell cycle. It is widely thought that specific complexes are required to traverse a point of commitment to the cell cycle in G1, and to promote S-phase and mitosis, respectively. Thus, according to a popular model that has dominated the field for decades, the inherent specificity of distinct CDK–cyclin complexes for different substrates at each phase of the cell cycle generates the correct order and timing of events. However, the results from the knockouts of genes encoding cyclins and CDKs do not support this model. An alternative “quantitative” model, validated by much recent work, suggests that it is the overall level of CDK activity (with the opposing input of phosphatases) that determines the timing and order of S-phase and mitosis. We take this model further by suggesting that the subdivision of the cell cycle into discrete phases (G0, G1, S, G2, and M) is outdated and problematic. Instead, we revive the “continuum” model of the cell cycle and propose that a combination with the quantitative model better defines a conceptual framework for understanding cell cycle control. Full article
(This article belongs to the Special Issue The Regulation of the Cell Cycle)
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12 pages, 2453 KiB  
Review
A Journey through Time on the Discovery of Cell Cycle Regulation
by Rustem Uzbekov and Claude Prigent
Cells 2022, 11(4), 704; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040704 - 17 Feb 2022
Cited by 16 | Viewed by 6376
Abstract
All living organisms on Earth are made up of cells, which are the functional unit of life. Eukaryotic organisms can consist of a single cell (unicellular) or a group of either identical or different cells (multicellular). Biologists have always been fascinated by how [...] Read more.
All living organisms on Earth are made up of cells, which are the functional unit of life. Eukaryotic organisms can consist of a single cell (unicellular) or a group of either identical or different cells (multicellular). Biologists have always been fascinated by how a single cell, such as an egg, can give rise to an entire organism, such as the human body, composed of billions of cells, including hundreds of different cell types. This is made possible by cell division, whereby a single cell divides to form two cells. During a symmetric cell division, a mother cell produces two daughter cells, while an asymmetric cell division results in a mother and a daughter cell that have different fates (different morphologies, cellular compositions, replicative potentials, and/or capacities to differentiate). In biology, the cell cycle refers to the sequence of events that a cell must go through in order to divide. These events, which always occur in the same order, define the different stages of the cell cycle: G1, S, G2, and M. What is fascinating about the cell cycle is its universality, and the main reason for this is that the genetic information of the cell is encoded by exactly the same molecular entity with exactly the same structure: the DNA double helix. Since both daughter cells always inherit their genetic information from their parent cell, the underlying fundamentals of the cell cycle—DNA replication and chromosome segregation—are shared by all organisms. This review goes back in time to provide a historical summary of the main discoveries that led to the current understanding of how cells divide and how cell division is regulated to remain highly reproducible. Full article
(This article belongs to the Special Issue The Regulation of the Cell Cycle)
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