How the Timing of Biological Processes Is Controlled and Modified at the Molecular and Cellular Level? 2.0

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Cell Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 23703

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Guest Editor
Dynamics and Mechanics of Epithelia Group, Faculty of Medicine, Institute of Genetics and Development of Rennes, University of Rennes, CNRS, UMR 6290, 35043 Rennes, France
Interests: embryo development; cell cycle; gene regulation; cancer; stem cells; gonads; genetic diseases
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Guest Editor
Transplant Immunology, The Houston Methodist Research Institute, Houston, TX 77030, USA
Interests: macrophages; actin cytoskeleton; RhoA pathway; chronic rejection; transplantation; germ cells; stem cells; Xenopus laevis; development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The correct timing of molecular and cellular events is critical for embryo development, cell/tissue homeostasis, and functions in all organisms. One example of this importance is the temporal regulation of cell cycle events. The cell cycle has to proceed in a well-defined time frame to assure, for example, the coordination between cell proliferation and the embryo developmental program. The checkpoint mechanisms monitor if the necessary processes have been completed before starting the new ones. Thus, the precise timely coordination between molecular pathways and their specific regulation in different conditions allows the harmonious functioning of cells, tissues, and organs. Another example is a circadian rhythm, which refers to any biological process occurring with an approximately 24-hour oscillation. As all aspects of cell physiology require a precise time control, the defects in this control may contribute to a number of diseases, including cancers, diabetes, and metabolic or behavioral disorders, and many more.

For this Special Issue, we invite research articles and review articles on all aspects of temporal regulation in cells and tissues, and particularly those which contribute to our understanding of the role of the time-dependent coordination between molecular pathways in physiological vs. pathological conditions. We hope that colleagues from many different fields of biology and medicine who are interested in the research question “How the Timing of Biological Processes Is Controlled and Modified at the Molecular and Cellular Level? 2.0” will contribute to this Special Issue.

Prof. Dr. Jacek Z Kubiak
Prof. Dr. Malgorzata Kloc
Guest Editors

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Keywords

  • timing regulation
  • molecular processes
  • cellular processes
  • cell cycle
  • circadian rhythm
  • embryo development
  • metabolism
  • cancer
  • diabetes

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Published Papers (10 papers)

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Editorial

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4 pages, 182 KiB  
Editorial
How the Timing of Biological Processes Is Controlled and Modified at the Molecular and Cellular Level? 2.0
by Jacek Z. Kubiak and Małgorzata Kloc
Biology 2024, 13(3), 170; https://doi.org/10.3390/biology13030170 - 07 Mar 2024
Viewed by 856
Abstract
The correct timing of molecular and cellular events is critical for embryo development, cell/tissue homeostasis, and to functions in all organisms throughout their whole lives [...] Full article

Research

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16 pages, 3451 KiB  
Article
Modeling the Circadian Control of the Cell Cycle and Its Consequences for Cancer Chronotherapy
by Courtney Leung, Claude Gérard and Didier Gonze
Biology 2023, 12(4), 612; https://doi.org/10.3390/biology12040612 - 18 Apr 2023
Cited by 4 | Viewed by 1363
Abstract
The mammalian cell cycle is governed by a network of cyclin/Cdk complexes which signal the progression into the successive phases of the cell division cycle. Once coupled to the circadian clock, this network produces oscillations with a 24 h period such that the [...] Read more.
The mammalian cell cycle is governed by a network of cyclin/Cdk complexes which signal the progression into the successive phases of the cell division cycle. Once coupled to the circadian clock, this network produces oscillations with a 24 h period such that the progression into each phase of the cell cycle is synchronized to the day–night cycle. Here, we use a computational model for the circadian clock control of the cell cycle to investigate the entrainment in a population of cells characterized by some variability in the kinetic parameters. Our numerical simulations showed that successful entrainment and synchronization are only possible with a sufficient circadian amplitude and an autonomous period close to 24 h. Cellular heterogeneity, however, introduces some variability in the entrainment phase of the cells. Many cancer cells have a disrupted clock or compromised clock control. In these conditions, the cell cycle runs independently of the circadian clock, leading to a lack of synchronization of cancer cells. When the coupling is weak, entrainment is largely impacted, but cells maintain a tendency to divide at specific times of day. These differential entrainment features between healthy and cancer cells can be exploited to optimize the timing of anti-cancer drug administration in order to minimize their toxicity and to maximize their efficacy. We then used our model to simulate such chronotherapeutic treatments and to predict the optimal timing for anti-cancer drugs targeting specific phases of the cell cycle. Although qualitative, the model highlights the need to better characterize cellular heterogeneity and synchronization in cell populations as well as their consequences for circadian entrainment in order to design successful chronopharmacological protocols. Full article
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20 pages, 3682 KiB  
Article
HN1 Is Enriched in the S-Phase, Phosphorylated in Mitosis, and Contributes to Cyclin B1 Degradation in Prostate Cancer Cells
by Aadil Javed, Gülseren Özduman, Lokman Varışlı, Bilge Esin Öztürk and Kemal Sami Korkmaz
Biology 2023, 12(2), 189; https://doi.org/10.3390/biology12020189 - 26 Jan 2023
Cited by 3 | Viewed by 2009
Abstract
HN1 has previously been shown as overexpressed in various cancers. In Prostate cancer, it regulates AR signaling and centrosome-related functions. Previously, in two different studies, HN1 expression has been observed as inversely correlated with Cyclin B1. However, HN1 interacting partners and the role [...] Read more.
HN1 has previously been shown as overexpressed in various cancers. In Prostate cancer, it regulates AR signaling and centrosome-related functions. Previously, in two different studies, HN1 expression has been observed as inversely correlated with Cyclin B1. However, HN1 interacting partners and the role of HN1 interactions in cell cycle pathways have not been completely elucidated. Therefore, we used Prostate cancer cell lines again and utilized both transient and stable inducible overexpression systems to delineate the role of HN1 in the cell cycle. HN1 characterization was performed using treatments of kinase inhibitors, western blotting, flow cytometry, immunofluorescence, cellular fractionation, and immunoprecipitation approaches. Our findings suggest that HN1 overexpression before mitosis (post-G2), using both transient and stable expression systems, leads to S-phase accumulation and causes early mitotic exit after post-G2 overexpression. Mechanistically, HN1 interacted with Cyclin B1 and increased its degradation via ubiquitination through stabilized Cdh1, which is a co-factor of the APC/C complex. Stably HN1-expressing cells exhibited a reduced Cdt1 loading onto chromatin, demonstrating an exit from a G1 to S phenotype. We found HN1 and Cdh1 interaction as a new regulator of the Cyclin B1/CDK1 axis in mitotic regulation which can be explored further to dissect the roles of HN1 in the cell cycle. Full article
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12 pages, 1185 KiB  
Article
The Dynamics of miR-449a/c Expression during Uterine Cycles Are Associated with Endometrial Development
by Mladen Naydenov, Maria Nikolova, Apostol Apostolov, Ilias Glogovitis, Andres Salumets, Vesselin Baev and Galina Yahubyan
Biology 2023, 12(1), 55; https://doi.org/10.3390/biology12010055 - 29 Dec 2022
Cited by 3 | Viewed by 1696
Abstract
The human endometrium is a highly dynamic tissue. Increasing evidence has shown that microRNAs (miRs) play essential roles in human endometrium development. Our previous assay, based on small RNA-sequencing (sRNA-seq) indicated the complexity and dynamics of numerous sequence variants of miRs (isomiRs) that [...] Read more.
The human endometrium is a highly dynamic tissue. Increasing evidence has shown that microRNAs (miRs) play essential roles in human endometrium development. Our previous assay, based on small RNA-sequencing (sRNA-seq) indicated the complexity and dynamics of numerous sequence variants of miRs (isomiRs) that can act together to control genes of functional relevance to the receptive endometrium (RE). Here, we used a greater average depth of sRNA-seq to detect poorly expressed small RNAs. The sequencing data confirmed the up-regulation of miR-449c and uncovered other members of the miR-449 family up-regulated in RE—among them miR-449a, as well as several isoforms of both miR-449a and miR-449c, while the third family member, miR-449b, was not identified. Stem-looped RT-qPCR analysis of miR expression at four-time points of the endometrial cycle verified the increased expression of the miR-449a/c family members in RE, among which the 5′ isoform of miR-449c–miR-449c.1 was the most strongly up-regulated. Moreover, we found in a case study that the expression of miR-449c.1 and its precursor correlated with the histological assessment of the endometrial phase and patient age. We believe this study will promote the clinical investigation and application of the miR-449 family in the diagnosis and prognosis of human reproductive diseases. Full article
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17 pages, 1750 KiB  
Article
eIF4B mRNA Translation Contributes to Cleavage Dynamics in Early Sea Urchin Embryos
by Florian Pontheaux, Sandrine Boulben, Héloïse Chassé, Agnès Boutet, Fernando Roch, Julia Morales and Patrick Cormier
Biology 2022, 11(10), 1408; https://doi.org/10.3390/biology11101408 - 27 Sep 2022
Cited by 2 | Viewed by 1496
Abstract
During the first steps of sea urchin development, fertilization elicits a marked increase in protein synthesis essential for subsequent cell divisions. While the translation of mitotic cyclin mRNAs is crucial, we hypothesized that additional mRNAs must be translated to finely regulate the onset [...] Read more.
During the first steps of sea urchin development, fertilization elicits a marked increase in protein synthesis essential for subsequent cell divisions. While the translation of mitotic cyclin mRNAs is crucial, we hypothesized that additional mRNAs must be translated to finely regulate the onset into mitosis. One of the maternal mRNAs recruited onto active polysomes at this stage codes for the initiation factor eIF4B. Here, we show that the sea urchin eIF4B orthologs present the four specific domains essential for eIF4B function and that Paracentrotus lividus eIF4B copurifies with eIF4E in a heterologous system. In addition, we investigated the role of eIF4B mRNA de novo translation during the two first embryonic divisions of two species, P. lividus and Sphaerechinus granularis. Our results show that injection of a morpholino directed against eIF4B mRNA results in a downregulation of translational activity and delays cell division in these two echinoids. Conversely, injection of an mRNA encoding for P. lividus eIF4B stimulates translation and significantly accelerates cleavage rates. Taken together, our findings suggest that eIF4B mRNA de novo translation participates in a conserved regulatory loop that contributes to orchestrating protein synthesis and modulates cell division rhythm during early sea urchin development. Full article
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11 pages, 1359 KiB  
Article
Magnetic Fluctuations Entrain the Circadian Rhythm of Locomotor Activity in Zebrafish: Can Cryptochrome Be Involved?
by Viacheslav V. Krylov, Evgeny I. Izvekov, Vera V. Pavlova, Natalia A. Pankova and Elena A. Osipova
Biology 2022, 11(4), 591; https://doi.org/10.3390/biology11040591 - 13 Apr 2022
Cited by 6 | Viewed by 2499
Abstract
In the 1960s, it was hypothesized that slow magnetic fluctuations could be a secondary zeitgeber for biological circadian rhythms. However, no comprehensive experimental research has been carried out to test the entrainment of free-running circadian rhythms by this zeitgeber. We studied the circadian [...] Read more.
In the 1960s, it was hypothesized that slow magnetic fluctuations could be a secondary zeitgeber for biological circadian rhythms. However, no comprehensive experimental research has been carried out to test the entrainment of free-running circadian rhythms by this zeitgeber. We studied the circadian patterns of the locomotor activity of zebrafish (Danio rerio) under different combinations of light regimes and slow magnetic fluctuations, based on a record of natural geomagnetic variation. A rapid synchronization of activity rhythms to an unusual 24:12 light/dark cycle was found under magnetic fluctuations with a period of 36 h. Under constant illumination, significant locomotor activity rhythms with 26.17 h and 33.07 h periods were registered in zebrafish exposed to magnetic fluctuations of 26.8 h and 33.76 h, respectively. The results reveal the potential of magnetic fluctuations for entrainment of circadian rhythms in zebrafish and genuine prospects to manipulate circadian oscillators via magnetic fields. The putative mechanisms responsible for the entrainment are discussed, including the possible role of cryptochromes. Full article
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Review

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15 pages, 834 KiB  
Review
CDC6 as a Key Inhibitory Regulator of CDK1 Activation Dynamics and the Timing of Mitotic Entry and Progression
by Mohammed El Dika, Damian Dudka, Malgorzata Kloc and Jacek Z. Kubiak
Biology 2023, 12(6), 855; https://doi.org/10.3390/biology12060855 - 14 Jun 2023
Cited by 1 | Viewed by 1833
Abstract
Timely mitosis is critically important for early embryo development. It is regulated by the activity of the conserved protein kinase CDK1. The dynamics of CDK1 activation must be precisely controlled to assure physiologic and timely entry into mitosis. Recently, a known S-phase regulator [...] Read more.
Timely mitosis is critically important for early embryo development. It is regulated by the activity of the conserved protein kinase CDK1. The dynamics of CDK1 activation must be precisely controlled to assure physiologic and timely entry into mitosis. Recently, a known S-phase regulator CDC6 emerged as a key player in mitotic CDK1 activation cascade in early embryonic divisions, operating together with Xic1 as a CDK1 inhibitor upstream of the Aurora A and PLK1, both CDK1 activators. Herein, we review the molecular mechanisms that underlie the control of mitotic timing, with special emphasis on how CDC6/Xic1 function impacts CDK1 regulatory network in the Xenopus system. We focus on the presence of two independent mechanisms inhibiting the dynamics of CDK1 activation, namely Wee1/Myt1- and CDC6/Xic1-dependent, and how they cooperate with CDK1-activating mechanisms. As a result, we propose a comprehensive model integrating CDC6/Xic1-dependent inhibition into the CDK1-activation cascade. The physiological dynamics of CDK1 activation appear to be controlled by the system of multiple inhibitors and activators, and their integrated modulation ensures concomitantly both the robustness and certain flexibility of the control of this process. Identification of multiple activators and inhibitors of CDK1 upon M-phase entry allows for a better understanding of why cells divide at a specific time and how the pathways involved in the timely regulation of cell division are all integrated to precisely tune the control of mitotic events. Full article
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11 pages, 836 KiB  
Review
Giant Multinucleated Cells in Aging and Senescence—An Abridgement
by Malgorzata Kloc, Ahmed Uosef, Arijita Subuddhi, Jacek Z. Kubiak, Rafal P. Piprek and Rafik M. Ghobrial
Biology 2022, 11(8), 1121; https://doi.org/10.3390/biology11081121 - 27 Jul 2022
Cited by 9 | Viewed by 3024
Abstract
This review introduces the subject of senescence, aging, and the formation of senescent multinucleated giant cells. We define senescence and aging and describe how molecular and cellular senescence leads to organismal senescence. We review the latest information on senescent cells’ cellular and molecular [...] Read more.
This review introduces the subject of senescence, aging, and the formation of senescent multinucleated giant cells. We define senescence and aging and describe how molecular and cellular senescence leads to organismal senescence. We review the latest information on senescent cells’ cellular and molecular phenotypes. We describe molecular and cellular features of aging and senescence and the role of multinucleated giant cells in aging-related conditions and cancer. We explain how multinucleated giant cells form and their role in aging arteries and gonads. We also describe how multinucleated giant cells and the reversibility of senescence initiate cancer and lead to cancer progression and metastasis. We also describe molecules and pathways regulating aging and senescence in model systems and their applicability to clinical therapies in age-related diseases. Full article
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16 pages, 752 KiB  
Review
S Phase Duration Is Determined by Local Rate and Global Organization of Replication
by Avraham Greenberg and Itamar Simon
Biology 2022, 11(5), 718; https://doi.org/10.3390/biology11050718 - 07 May 2022
Cited by 6 | Viewed by 2882
Abstract
The duration of the cell cycle has been extensively studied and a wide degree of variability exists between cells, tissues and organisms. However, the duration of S phase has often been neglected, due to the false assumption that S phase duration is relatively [...] Read more.
The duration of the cell cycle has been extensively studied and a wide degree of variability exists between cells, tissues and organisms. However, the duration of S phase has often been neglected, due to the false assumption that S phase duration is relatively constant. In this paper, we describe the methodologies to measure S phase duration, summarize the existing knowledge about its variability and discuss the key factors that control it. The local rate of replication (LRR), which is a combination of fork rate (FR) and inter-origin distance (IOD), has a limited influence on S phase duration, partially due to the compensation between FR and IOD. On the other hand, the organization of the replication program, specifically the amount of replication domains that fire simultaneously and the degree of overlap between the firing of distinct replication timing domains, is the main determinant of S phase duration. We use these principles to explain the variation in S phase length in different tissues and conditions. Full article
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24 pages, 1300 KiB  
Review
Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks
by Yool Lee and Jonathan P. Wisor
Biology 2022, 11(1), 21; https://doi.org/10.3390/biology11010021 - 24 Dec 2021
Cited by 14 | Viewed by 4370
Abstract
The circadian clock is a fundamental biological timing mechanism that generates nearly 24 h rhythms of physiology and behaviors, including sleep/wake cycles, hormone secretion, and metabolism. Evolutionarily, the endogenous clock is thought to confer living organisms, including humans, with survival benefits by adapting [...] Read more.
The circadian clock is a fundamental biological timing mechanism that generates nearly 24 h rhythms of physiology and behaviors, including sleep/wake cycles, hormone secretion, and metabolism. Evolutionarily, the endogenous clock is thought to confer living organisms, including humans, with survival benefits by adapting internal rhythms to the day and night cycles of the local environment. Mirroring the evolutionary fitness bestowed by the circadian clock, daily mismatches between the internal body clock and environmental cycles, such as irregular work (e.g., night shift work) and life schedules (e.g., jet lag, mistimed eating), have been recognized to increase the risk of cardiac, metabolic, and neurological diseases. Moreover, increasing numbers of studies with cellular and animal models have detected the presence of functional circadian oscillators at multiple levels, ranging from individual neurons and fibroblasts to brain and peripheral organs. These oscillators are tightly coupled to timely modulate cellular and bodily responses to physiological and metabolic cues. In this review, we will discuss the roles of central and peripheral clocks in physiology and diseases, highlighting the dynamic regulatory interactions between circadian timing systems and multiple metabolic factors. Full article
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