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Event: 2202

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Altered expression of cell cycle genes

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Altered expression of cell cycle genes
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
RAR agonism during neurodevelopment leading to impaired learning and memory KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite
RAR agonism during neurodevelopment leading to microcephaly KeyEvent Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The eukaryotic cell cycle is divided into phases, comprising the interphase (G1, S, and G2) and the mitotic (M) phase. Under certain conditions, cells can exit the cycle and reversibly enter a state of quiescence (the G0 phase), terminally differentiate or enter a senescent state (Kumari and Jat 2021).

During cell division, the cells can progress through the cycle if they pass three major checkpoints (in G1-to-S, G2-to-M and M-to-G1), which ensure that the resulting daughter cells are healthy. The passage through successive phases is driven by cyclins and cyclin-dependent kinase (CDK) complexes (Murray, 2004). Cyclins are divided into 4 groups (A-, B-, D-, and E-cyclins) and CDKs include at least 11 proteins (Murray, 2004; Hochegger et al., 2008; Malumbres, 2009). However, there are two different perspectives as to how the cyclin-Cdk complexes temporally regulate events during the cell cycle (Hochegger et al., 2008). One model asserts that the correct completion of the S and M phases is brought about through different biochemical activities of cyclin-cdk heterodimers associated with each phase. In this view, the various cyclin-CDK complexes appear in a specific temporal sequence and target different substrates to drive progression through the cell cycle (van den Heuvel and Harlow, 1993; Sherr, 1993; Pagliuca et al., 2011). On the other hand, a second model proposes that it is the progressive increase in total CDK cell activity that drives the cell cycle, rather than CDK substrate specificity. In this view, substrates in the DNA replication phase are phosphorylated at a lower total CDK activity level than substrates in the mitotic phase (Swaffer et al., 2016). Recently, Basu et al., have reconciled these two opposing perspectives into a unitary framework which proposes a quantitative view of core CDK cell cycle control with a minor qualitative element (Basu et al., 2022). Using phosphoproteomics to study in vivo CDK activity in fission yeast, the authors show that cyclin-CDK complexes are not completely specialised for either S or M phase, and that increasing the CDK activity of S phase dimers is sufficient to carry out mitosis (Basu et al., 2022).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

How it is measured or detected

Expression of cyclins and Cdks at various phases of the cell cycle can be performed at the transcript or protein level. The mRNA content of specific cyclins and Cdks can be measured using qPCR, or in the context of a more global analysis using microarray or RNAseq methods (see for e.g. Karsten et al., 2003; Kowalczyk et al., 2015; Cheroni et al., 2022). The protein amount of individual Cdks, cyclins, as well as their phosphorylated forms can be detected using immunodetection methods such as western blotting or enzyme-linked immunosorbent assays (ELISAs), as well as through mass spectrometric approaches (see for e.g. Frisa and Jacobberger, 2009; Basu et al., 2022).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

References

List of the literature that was cited for this KE description. More help

1.                         Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol. 2021;9:645593.

2.                         Murray AW. Recycling the cell cycle: cyclins revisited. Cell. 2004;116(2):221-34.

3.                         Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol. 2008;9(11):910-6.

4.                         Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11(11):1275-6.

5.                         van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993;262(5142):2050-4.

6.                         Sherr CJ. Mammalian G1 cyclins. Cell. 1993;73(6):1059-65.

7.                         Pagliuca FW, Collins MO, Lichawska A, Zegerman P, Choudhary JS, Pines J. Quantitative proteomics reveals the basis for the biochemical specificity of the cell-cycle machinery. Mol Cell. 2011;43(3):406-17.

8.                         Swaffer MP, Jones AW, Flynn HR, Snijders AP, Nurse P. CDK Substrate Phosphorylation and Ordering the Cell Cycle. Cell. 2016;167(7):1750-61.e16.

9.                         Basu S, Greenwood J, Jones AW, Nurse P. Core control principles of the eukaryotic cell cycle. Nature. 2022;607(7918):381-6.

10.                       Karsten SL, Kudo LC, Jackson R, Sabatti C, Kornblum HI, Geschwind DH. Global analysis of gene expression in neural progenitors reveals specific cell-cycle, signaling, and metabolic networks. Dev Biol. 2003;261(1):165-82.

11.                       Kowalczyk MS, Tirosh I, Heckl D, Rao TN, Dixit A, Haas BJ, et al. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. Genome Res. 2015;25(12):1860-72.

12.                       Cheroni C, Trattaro S, Caporale N, López-Tobón A, Tenderini E, Sebastiani S, et al. Benchmarking brain organoid recapitulation of fetal corticogenesis. Transl Psychiatry. 2022;12(1):520.

13.                       Frisa PS, Jacobberger JW. Cell cycle-related cyclin b1 quantification. PLoS One. 2009;4(9):e7064