API

Relationship: 2077

Title

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Activation, Glucocorticoid Receptor leads to Increase, Cripto-1 expression

Upstream event

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Activation, Glucocorticoid Receptor

Downstream event

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Increase, Cripto-1 expression

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Glucocorticoid Receptor Agonism Leading to Impaired Fin Regeneration adjacent Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
zebrafish Danio rerio Moderate NCBI

Sex Applicability

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Sex Evidence
Mixed Moderate

Life Stage Applicability

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Term Evidence
larvae Moderate

Key Event Relationship Description

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  • The glucocorticoid receptor (GR) is a steroid receptor belonging to the nuclear receptor (NR) family of ligand-dependent transcription factors. In the absence of a ligand, the GR is transcriptionally inactive in the cytoplasm. 
  • Cripto-1 is responsible for growth factor activity, as well as activin binding on the cell membrane.  Cripto-1  may also be referred to as teratocarcinoma-derived growth factor 1, tdgf1, or one-eyed pinhead protein, depending on the species (Uniprot).
  • It is believed that GR is a transcription factor that helps to regulate Cripto-1

Evidence Supporting this KER

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Biological Plausibility

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It is believed that GR is a transcription factor that helps to regulate Cripto-1

Empirical Evidence

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  • Sengupta et al (2012) exposed larval zebrafish to known glucocorticoid receptor agonists; dexamethasone, hydrocortisone, and beclomethasone dipropionate at 1µM. Relative abundance of annexin a1b – a glucocorticoid receptor regulated gene – was decreased in all treatments compared to a DMSO control, indicating glucocorticoid receptor was activated. A significant increase in the expression cripto-1 was also observed in fish exposed to beclomethasone dipropionate.
  • Garland et al (2019) saw increases in cripto-1 expression after exposing zebrafish larvae (2dpf) to 1uM beclomethasone in 0.1% DMSO for 3 days following caudal fin amputation. Expression of cripto-1 increased 8.5-fold compared to fish exposed to 0.1% DMSO as a control.

Uncertainties and Inconsistencies

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  • Increases in cripto-1 expression are dependent on the structure or potency of the GR-Agonist used during exposure. Well-known GR-agonists such as Dexamethasone, hydrocortisone, and beclomethasone have no effect on cripto-1 expression at 1µM while beclomethasone dipropionate does. (Sengupta et al., 2012).
  • Due to a lack of evidence for different life stages, increases in cripto-1 expression can only be assumed in larval fish.

Quantitative Understanding of the Linkage

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Data to characterize the quantitative relationship between GR activation and cripto-1 express is currently lacking.

Response-response Relationship

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Not yet evaluated.

Time-scale

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Not yet evaluated.

Known modulating factors

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Not yet evaluated.

Known Feedforward/Feedback loops influencing this KER

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Not yet evaluated.

Domain of Applicability

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Due to limited evidence, the relationship between GR and Cripto-1 is only known in Zebrafish (Garland et al., 2019). However, GR is fairly conserved across species (Stolte et al., 2006) as is cripto-1 (Ravisankar et al., 2011). The activation of GR may have a similar outcome dependant on the sensitivity of the receptor (Stolte et al., 2006). It can be presumed that the relationship between GR and cripto-1 is conserved across teleost with the exception of receptor sensitivity. 

References

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Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. Glucocorticoid receptor-dependent induction of cripto-1 (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013

Ravisankar V, Signh TP, Manoj N. 2011. Molecular evolution of the EGF-CFC protein family. Gene, 428:43-50. doi:10.1016/j.gene.2011.05.007

Sengupta S, Bisson WH, Mathew LK, Kolluri SK, Tanguay RL. 2012. Alternative glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model. Comparative Biochemistry and Physiology, Part C 156:121-129. doi:10.1016/j.cbpc.2012.05.003

Solte EH, Lidy Verberg van Kemenade BM, Savelkoul FJ, Flik G. 2006. Evolution of glucocorticoid receptors with different glucocorticoid sensitivity. Journal of Endocrinology 190:17-28. DOI: 10.1677/joe.1.06703