API

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Relationship: 3109

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

RAR agonism leads to Altered expression of cell cycle genes

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
RAR agonism
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Altered expression of cell cycle genes

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
Retinoic acid receptor agonism during neurodevelopment leading to impaired learning and memory adjacent High Not Specified Diana Lupu (send email) Under development: Not open for comment. Do not cite
Retinoic acid receptor agonism during neurodevelopment leading to microcephaly adjacent High Not Specified Diana Lupu (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 Do not cite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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

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

Life Stage Applicability

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

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

Retinoic acid receptors (RARs) can function as ligand-dependent transcriptional regulators of target genes involved in cellular differentiation, proliferation and apoptosis (Gudas and Wagner 2011; Noy 2010), and therefore play crucial roles in a multitude of biological processes, such as embryonic and fetal development, including cardiovascular, respiratory and CNS development, reproduction and immunity (reviewed in Mark et al., 2009; McCaffery and Dräger 2000; Clagett-Dame and Knutson 2011; Damdimopoulou 2019; Erkelens and Mebius 2017). 

The repertoire of target genes that can be regulated by RARs is cell-specific and additionally depends on the presence of receptor ligands (Delacroix et al., 2010; Mahony et al., 2011). Several genes regulated by RARs, including those within the retinoid pathway such as Rarb, Crbp1/2 (Rbp1/2), Crabp1/2, and Cyp26a1, have been identified (reviewed in Balmer and Blomhoff, 2002). Additionally, members of the Hox gene family, such as Hoxa1, Hoxb1, Hoxb4, and Hoxd4, contain RAREs, with demonstrated in vivo functionality (reviewed in Glover et al., 2006). 

Retinoic acid (RA) regulation of the cell cycle and related genes has been studied in various cancer cells, where RA is able to induce cell cycle arrest and apoptosis (Lotan et al., 1978; Thiele et al., 1985; Mangiarotti et al., 1998; Hsu et al., 2000; Dimberg et al., 2002; Chen and Ross, 2004; Donato et al., 2007; Lin et al., 2014; Zhang et al., 2014). Likewise, RA has been shown to promote cell cycle exit and differentiation of mouse pluripotent (Kim et al., 2009), as well as various multipotent cells such as mouse embryonic palatal mesenchymal (MEPM) cells (Yu et al., 2005), mouse and human hemogenic endothelial cells (Qiu et al., 2020), mouse and human neural progenitor cells (Wohl and Weiss, 1998; Koch et al., manuscript in preparation; Culbreth et al., 2012).

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

Cell cycle genes regulated directly or indirectly by RA, the endogenous RAR agonist, include cyclins (e.g. cyclins A1, B1, B2, C, E, E1, E2, D1, D2, D3), cyclin-dependent kinases (e.g. CDK2, CDK4, CDK5, CDK6, CDK10, CDK14, CDK18, CDK19) and cyclin-dependent kinase inhibitors (e.g. CDKN1A, CDKN2A, CDKN1B, CDKN1C, CDKN2C)  (Duffy et al., 2017; Li et al., 2003; Wang et al., 2017; Donato et al., 2007; Delacroix et al., 2010; Terranova et al., 2015).

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
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

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
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

References

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

1.                   Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011;226(2):322-30.

2.                   Noy N. Between death and survival: retinoic acid in regulation of apoptosis. Annu Rev Nutr. 2010;30:201-17.

3.                   Mark M, Ghyselinck NB, Chambon P. Function of retinoic acid receptors during embryonic development. Nucl Recept Signal. 2009;7:e002.

4.                   Clagett-Dame M, Knutson D. Vitamin A in reproduction and development. Nutrients. 2011;3(4):385-428.

5.                   Damdimopoulou P, Chiang C, Flaws JA. Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis. Reprod Toxicol. 2019;87:32-41.

6.                   Erkelens MN, Mebius RE. Retinoic Acid and Immune Homeostasis: A Balancing Act. Trends Immunol. 2017;38(3):168-80.

7.                   Delacroix L, Moutier E, Altobelli G, Legras S, Poch O, Choukrallah MA, et al. Cell-specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells. Mol Cell Biol. 2010;30(1):231-44.

8.                   Mahony S, Mazzoni EO, McCuine S, Young RA, Wichterle H, Gifford DK. Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol. 2011;12(1):R2.

9.                   Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res. 2002;43(11):1773-808.

10.                 Glover JC, Renaud JS, Rijli FM. Retinoic acid and hindbrain patterning. J Neurobiol. 2006;66(7):705-25.

11.                 Lotan R, Giotta G, Nork E, Nicolson GL. Characterization of the inhibitory effects of retinoids on the in vitro growth of two malignant murine melanomas. J Natl Cancer Inst. 1978;60(5):1035-41.

12.                 Thiele CJ, Reynolds CP, Israel MA. Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. Nature. 1985;313(6001):404-6.

13.                 Mangiarotti R, Danova M, Alberici R, Pellicciari C. All-trans retinoic acid (ATRA)-induced apoptosis is preceded by G1 arrest in human MCF-7 breast cancer cells. Br J Cancer. 1998;77(2):186-91.

14.                 Hsu SL, Hsu JW, Liu MC, Chen LY, Chang CD. Retinoic acid-mediated G1 arrest is associated with induction of p27(Kip1) and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells. Exp Cell Res. 2000;258(2):322-31.

15.                 Dimberg A, Bahram F, Karlberg I, Larsson LG, Nilsson K, Oberg F. Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional up-regulation of p27(Kip1). Blood. 2002;99(6):2199-206.

16.                 Chen Q, Ross AC. Retinoic acid regulates cell cycle progression and cell differentiation in human monocytic THP-1 cells. Exp Cell Res. 2004;297(1):68-81.

17.                 Donato LJ, Suh JH, Noy N. Suppression of mammary carcinoma cell growth by retinoic acid: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling. Cancer Res. 2007;67(2):609-15.

18.                 Lin E, Chen MC, Huang CY, Hsu SL, Huang WJ, Lin MS, et al. All-trans retinoic acid induces DU145 cell cycle arrest through Cdk5 activation. Cell Physiol Biochem. 2014;33(6):1620-30.

19.                 Zhang ML, Tao Y, Zhou WQ, Ma PC, Cao YP, He CD, et al. All-trans retinoic acid induces cell-cycle arrest in human cutaneous squamous carcinoma cells by inhibiting the mitogen-activated protein kinase-activated protein 1 pathway. Clin Exp Dermatol. 2014;39(3):354-60.

20.                 Kim M, Habiba A, Doherty JM, Mills JC, Mercer RW, Huettner JE. Regulation of mouse embryonic stem cell neural differentiation by retinoic acid. Dev Biol. 2009;328(2):456-71.

21.                 Yu Z, Lin J, Xiao Y, Han J, Zhang X, Jia H, et al. Induction of cell-cycle arrest by all-trans retinoic acid in mouse embryonic palatal mesenchymal (MEPM) cells. Toxicol Sci. 2005;83(2):349-54.

22.                 Qiu J, Nordling S, Vasavada HH, Butcher EC, Hirschi KK. Retinoic Acid Promotes Endothelial Cell Cycle Early G1 State to Enable Human Hemogenic Endothelial Cell Specification. Cell Rep. 2020;33(9):108465.

23.                 Wohl CA, Weiss S. Retinoic acid enhances neuronal proliferation and astroglial differentiation in cultures of CNS stem cell-derived precursors. J Neurobiol. 1998;37(2):281-90.

24.                 Culbreth ME, Harrill JA, Freudenrich TM, Mundy WR, Shafer TJ. Comparison of chemical-induced changes in proliferation and apoptosis in human and mouse neuroprogenitor cells. Neurotoxicology. 2012;33(6):1499-510.

25.                 Duffy DJ, Krstic A, Halasz M, Schwarzl T, Konietzny A, Iljin K, et al. Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance. Genome Med. 2017;9(1):15.

26.                 Li A, Zhu X, Brown B, Craft CM. Gene expression networks underlying retinoic acid-induced differentiation of human retinoblastoma cells. Invest Ophthalmol Vis Sci. 2003;44(3):996-1007.

27.                 Wang X, Dasari S, Nowakowski GS, Lazaridis KN, Wieben ED, Kadin ME, et al. Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma. Oncotarget. 2017;8(16):26245-55.

28.                 Terranova C, Narla ST, Lee YW, Bard J, Parikh A, Stachowiak EK, et al. Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1). PLoS One. 2015;10(4):e0123380.