PUBLICATION
Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish
- Authors
- Zhang, L., Kim, S.H., Park, K.H., Townsend, D., Tew, K.D.
- ID
- ZDB-PUB-210131-5
- Date
- 2021
- Source
- The Journal of pharmacology and experimental therapeutics 377(1): 121-132 (Journal)
- Registered Authors
- Tew, Kenneth, Townsend, Danyelle, Zhang, Leilei
- Keywords
- Endoplasmic reticulum stress, Gene editing/CRISPR, Glutathione S-transferase (GST)
- MeSH Terms
-
- 4-Aminobenzoic Acid/toxicity
- Activating Transcription Factor 4/genetics
- Activating Transcription Factor 4/metabolism
- Animals
- Extracellular Signal-Regulated MAP Kinases/genetics
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Glutathione S-Transferase pi/genetics
- Glutathione S-Transferase pi/metabolism*
- Homeostasis
- Larva/drug effects
- Larva/metabolism
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/metabolism
- Nitric Oxide/toxicity
- Oxidants/toxicity
- Oxidation-Reduction
- Transcriptome
- Tunicamycin/toxicity
- Unfolded Protein Response*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 33514607 Full text @ J. Pharmacol. Exp. Ther.
Citation
Zhang, L., Kim, S.H., Park, K.H., Townsend, D., Tew, K.D. (2021) Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish. The Journal of pharmacology and experimental therapeutics. 377(1):121-132.
Abstract
We have created a novel glutathione S-transferase Pi 1 (gstp1) knockout (KO) zebrafish model and used it for comparative analyses of redox homeostasis, response to drugs that cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). Under basal conditions, gstp1 KO larvae had higher expression of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) accompanied by a more reduced larval environment and a status consistent with reductive stress. Compared to wild type (WT), various UPR markers were decreased in KO larvae, but treatment with drugs that induce ER stress caused greater toxicities and increased expression of Nrf2 and UPR markers in KO; tunicamycin (TuM) and 02-{2,4-dinitro-5-[4-(N-methylamino) benzoyloxy] phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate (PABA/NO) activated IRE1/XBP1 pathways, while thapsigargin (ThG) caused greater activation of PERK/ATF4/CHOP pathways. These results suggest that this teleost model is useful in predicting how GSTP regulates organismal management of oxidative/reductive stress and is a determinant of response to drug-induced ER stress and the UPR. Significance Statement A new zebrafish model has been created to study the importance of Gstp1 in development, redox homeostasis and response to drugs that enact cytotoxicity through ER-stress and induction of the UPR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping