API

This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1711

Title

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

p21 (CDKN1A) expression, increase leads to Cell cycle, disrupted

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
p21 (CDKN1A) expression, increase
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Cell cycle, disrupted

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

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
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High 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 regulation through p21 (cyclin dependent kinase inhibitor 1A; CDKN1A) activation is demonstrated by the interactions of p21 with cyclins [Dotto, 2000]. p21 interacts directly with cyclins through a conserved region in close to its N-terminus (amino acids 17-24; Cy1) [Dotto, 2000]. The cyclin dependent kinase inhibitor, p21 has the secondary weak cyclin binding domain near its C-terminus region (amino acids 153-159), which overlaps with its proliferating cell nuclear antigen (PCNA) binding domain [Dotto, 2000]. Kinase activity of cyclin-dependent kinase (Cdk) was inhibited by Cy1 site of p21 that is important for the interaction of p21 with cyclin-Cdk complexes [Chen, 1996]. The p21 inhibits Cdk complexes such as cyclin A/E-Cdk2 or cyclin D-Cdk4 complexes, leading to the cell cycle disruption as G1/S arrest [Chen, 1996].

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 Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

TSA promotes apoptosis via HDAC inhibition and p53 signaling pathway activation [Deng, 2016a]. It is suggested that furazolidone induces reactive oxygen species leading to suppression of p-AKT and p21, and induction of apoptosis [Deng, 2016b]. The dual roles of p21 in cell cycle arrest and anti-apoptotic effect in the testicular germ cells of diabetic rats are suggested [Kilarkaje, 2015]. The anti-apoptotic effect of p21 is mediated by caspase-3 inhibition, which demonstrates the possibility of cell-cycle independent effect on apoptosis [Deng, 2016b]. It has been demonstrated that p21 induces apoptosis in human cervical cancer cell lines [Tsao, 1999], whereas p21 is implicated in apoptosis inhibition by blocking activation of caspase-3 or interacting with ASK1 [Gartel, 2002, Zhan, 2007]. Up-regulation of p21 is implicated in the activation of DNA damage pathways, and deletion of p21 improved stem cell function and lifespan without accelerating chromosomal instability, which indicates that p21-dependent checkpoint induction affects the longevity limit [Choudhury, 2007].

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

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

DNA replication in Xenopus was suppressed by the GST fusion protein of p21 without amino acids 17-24 or the peptide containing cyclin binding site in N-terminus of p21 protein [Chen, 1996]. P21 regulates the E2F transcriptional activity to control cell cycle in human U2OS osteosarcoma cells (Homo sapiens) [Delavaine, 1999]. Cell cycle is regulated by p21 through cyclins and CDKs in mice (Mus musculus) [Sherr CJ, 2004].