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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 Supporting this KER

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

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

p21 has a separate cyclin-dependent kinase 2 (CDK2) binding site in its N-terminus region (amino acids 53-58) and optimal cyclin/CDK inhibition requires binding by this site as well as one of the cyclin binding sites [Dotto, 2000]. The peptide containing Cy1 site inhibited the kinase activity of cyclin E-Cdk2 and cyclin A-Cdk2 [Chen, 1996]. The p21^{WAF1/CIP1/sdi1} gene product inhibits the cyclin D/cdk4/6 and the cyclin E/cdk2 complexes in response to DNA-damage, resulting in G₁/S arrest [Moussa, 2015, Ogryzko, 1997]. p21 inhibits cyclin-dependent kinases and regulates cell cycle to promote cell cycle arrest. Deletion of either cyclin binding site in N-terminus or C-terminus of p21, or CDK binding domain was sufficient for the kinase activity inhibition [Chen, 1996].

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

TSA induces p21 expression leading to cell cycle arrest [Gartel, 2002].
The up-regulation of p21 signaling and in testicular germ cells was observed in diabetes [Kilarkaje, 2015].
A study investing the effects of miR-6734 that has a sequence homology with a specific region of p21^WAF1/CIP1 promoter on HCT-116 colon cancer cell growth indicated that miR-6734 up-regulated p21 gene expression and induced cell cycle arrest [Kang, 2016]. This result suggests that the direct enhancement of p21 gene expression is related to the alteration of the cell cycle distribution [Kang, 2016].
The study of postnatal telomere indicated that dysfunction of premature telomere induces cell-cycle arrest through p21 activation in mammalian cardiomyocytes [Aix, 2016].
The p21^{WAF1/CIP1/sdi1} gene product inhibits the cyclin D/cdk4/6 and the cyclin E/cdk2 complexes in response to DNA-damage, resulting in G₁/S arrest [Moussa, 2015, Ogryzko, 1997].

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

The peptide containing cyclin-binding domain of p21 in N-terminus inhibited the kinase activity of cyclin E-Cdk2 with 296 nM of the concentration in which kinase activity is inhibited in 50% (Ki) [Chen, 1996].

The peptide containing cyclin-binding domain of p21 in C-terminus showed 32,000, 800, or >300,000 nM of Ki for inhibition of the kinase activity of cyclin E-Cdk2, cyclin A-Cdk2 or cyclin D1-Cdk4, respectively [Chen, 1996].

Time-scale

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

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

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].

References

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

Dotto GP (2000) p21^WAF1/Cip1: more than a break to the cell cycle? Biochim Biophys Acta 1471: M43-M56

Chen J et al (1996) Cyclin-binding motifs are essential for the function of p21^CIP1. Mol Cell Biol 16: 4673-4682

Moussa RS et al. (2015) Differential targeting of the cyclin-dependent kinase inhibitor, p21CIP/WAF1, by chelators with anti-proliferative activity in a range of tumor cell-types. Oncotarget 6:29694-29711

Ogryzko VV et al. (1997) WAF1 retards S-phase progression primarily by inhibition of cyclin-dependent kinases. Mol Cell Biol 17:4877-4882

Gartel AL and Tyner AL (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1: 639-649

Kilarkaje N and Al-Bader MM. (2015) Diabetes-Induced Oxidative DNA Damage Alters p53-p21^CIP1/Waf1 Signaling in the Rat Testis. Reproductive Sciences 22: 102–112

Kang MR et al (2016) miR-6734 up-regulates p21 gene expression and induces cell cycle arrest and apoptosis in colon cancer cells. PLoS One 11: e0160961

Aix E et al (2016) Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation. J Cell Biol 213: 571-583

Deng Z et al. (2016a) Histone deacetylase inhibitor trichostatin A promotes the apoptosis of osteosarcoma cells through p53 signaling pathway activation. Int J Biol Sci 12:1298-1308

Deng S et al (2016b) P21^Waf1/Cip1 plays a critical role in furazolidone-induced apoptosis in HepG2 cells through influencing the caspase-3 activation and ROS generation. Food Chem Toxicol 88: 1-12

Tsao YP et al (1999) Adenovirus-mediated p21^{WAF1/SDII/CIP1} gene transfer induces apoptosis of human cervical cancer cell lines. J Virology 73: 4983-4990

Zhan J et al (2007) Negative regulation of ASK1 by p21Cip1 involves a small domain that includes serine 98 that is phosphorylated by ASK1 in vivo. Mol Cell Biol 27: 3530-3541

Choudhury AR et al (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39: 99-105

Delavaine L and La Thangue NB (1999) Control of E2F activity by p21Waf1/Cip1. Oncogene 18: 5381-5392

Sherr CJ and Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Gene Dev 18: 2699-2711