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Relationship: 1712


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Cell cycle, disrupted leads to Apoptosis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Histone deacetylase inhibition leading to testicular atrophy adjacent Moderate Moderate Brendan Ferreri-Hanberry (send email) Open for citation & comment WPHA/WNT Endorsed

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Oryctolagus cuniculus Oryctolagus cuniculus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Not Otherwise Specified High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cell cycle dysregulation may lead to apoptosis. Cell cycles characterized by the DNA content changes regulate cell death and cell proliferation [Lynch et al., 1986].

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The microRNA-497, potentially targeting Bcl-2 and cyclin D2 (CCND2), activated caspases 9/3, and induced apoptosis via the Bcl-2/Bax - caspase 9 - caspase 3 pathway and CCND2 protein in human umbilical vein endothelial cells (HUVECs) [Wu, 2016]. CCND2 is an important cell cycle gene, of which a decrease in expression induces G1 arrest [Li et al., 2012], and dysregulated CCND2 is implicated in cell proliferation inhibition [Wu et al., 2016; Mermelstein et al., 2005; Dong et al., 2010].

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The incidence of apoptosis was increased in vincristine-treated cells, in which metaphases were arrested, compared to untreated cells, which indicates that cell cycle dysregulation leads to apoptosis [Sarraf and Bowen, 1986]. Cell gain and loss are balanced with mitosis and apoptosis [Cree et al., 1987]. Apoptosis is mediated by caspase activation [Porter and Janicke, 1999]. Caspase-3 is activated in programmed cell death, and the pathways to caspase-3 activation include caspase-9 and mitochondrial cytochrome c release [Porter and Janicke, 1999]. The activation of caspase-3 leads to apoptotic chromatin condensation and DNA fragmentation [Porter and Janicke, 1999]. Sinularin, a marine natural compound, exhibited DNA damage and induced G2/M cell cycle arrest, followed by apoptosis in human hepatocellular carcinoma HepG2 cells [Chung et al., 2017]. Sinularin induced caspases 8, 9, and 3, and pro-apoptotic protein Bax, whereas it decreases the anti-apoptotic Bcl-2 protein expression level [Chung et al., 2017].


Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

MAA induces CDK4 and CDK2 decreases, cell cycle arrest, and apoptosis, which may be regulated by several pathways [Parajuli et al., 2014].

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Treatment with sinularin, a natural product isolated from cultured soft coral possessing antineoplastic activity, at 12.5, 25, 50 microM resulted in cell cycle disruption and apoptosis in a dose-dependent manner in hepatocellular carcinoma cells [Chun et al., 2017]. The cell cycle disruption and apoptosis are induced by 30 microM curcumin, a major component extracted from turmeric plants that have an anti-cancer effect [Liu et al., 2018].

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

MAA (5 mM) decreases CDK4, CDK2 expression 48 hrs after the treatment, which indicates the G1 arrest [Parajuli et al., 2014]. MAA (5 mM) decreases the protein expression of procaspase 7 and 3 in 24 to 72 hrs after the treatment, indicating the activation of caspases 7 and 3 [Parajuli et al., 2014].

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The relationship between disrupted cell cycle and apoptosis is likely well conserved between species. The examples are only given for mammals:

  • MicroRNA let-7a induced cell cycle arrest and inhibited CCND2 and proliferation of human prostate cancer cells (Homo sapiens) [Dong et al., 2010].
  • The microRNA-497 down-regulated CCND2 and induced apoptosis via the Bcl-2/Bax-caspase 9- caspase 3 pathway in HUVECs (Homo sapiens) [Wu et al., 2016].
  • The microRNA-26a regulated p53-mediated apoptosis and CCND2 and CCNE2 in mouse hepatocyte (Mus musculus) [Zhou et al., 2016].


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

Chung, T.W. et al. (2017), "Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells", BMC Complement Altern Med 17:62

Cree, I.A. et al. (1987), "Cell death in granulomata: the role of apoptosis", J Clin Pathol 40:1314-1319

Dong, Q. et al. (2010), "microRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2", PLoS One 5:e10147

Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257

Li, L. et al. (2012), "Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma", Lab Invest 92:571-583

Liu, W. et al. (2018), "Curcumin suppresses gastric cancer biological activity by regulation of miRNA-21: an in vitro study", Int J Clin Exp Pathol 11:5820-5289

Lynch, M.P. et al. (1986), "Evidence for soluble factors regulating cell death and cell proliferation in primary cultures of rabbit endometrial cells grown on collagen", Proc Natl Acad Sci USA 83:4784-4788

Mermelshtein, A. et al. (2005), "Expression of F-type cyclins in colon cancer and in cell lines from colon carcinomas", Br J Cancer 93:338-345

Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313

Porter, A.G. and Janicke, R.U. (1999), "Emerging roles of caspase-3 in apoptosis", Cell Death Differ 6:99-104

Sarraf, C.E. and Bowen, I.D. (1986), "Kinetic studies on a murine sarcoma and an analysis of apoptosis", Br J Cancer 54:989-998

Wu, R. et al. (2016), "microRNA-497 induces apoptosis and suppressed proliferation via the Bcl-2/Bax-caspase9-caspase 3 pathway and cyclin D2 protein in HUVECs", PLoS One 11:e0167052

Zhou, J. et al. (2016), "miR-26a regulates mouse hepatocyte proliferation via directly targeting the 3’ untranslated region of CCND2 and CCNE2", Hepatobiliary Pancreat Dis Int 15:65-72