Biology subjects

Willmore, W. G.

Publications and source records attributed to Willmore, W. G..

2 recordsLinked to original sources

bioRxiv2024

Crosstalk between the aryl hydrocarbon receptor and hypoxia inducible factor 1α pathways impairs downstream dioxin response in human islet models

The incidence of type 2 diabetes (T2D) is increasing globally at a rate that cannot be explained solely by genetic predisposition, diet, or lifestyle. Epidemiology studies report positive associations between exposure to persistent organic pollutants, such as dioxins, and T2D. We previously showed that 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) activates the xenobiotic-sensitive aryl hydrocarbon receptor (AHR) in pancreatic islets. The AHR is known to crosstalk with the hypoxia inducible factor 1 (HIF1) in hepatocytes but whether this crosstalk occurs in islet cells remains unknown. We assessed AHR-HIF1 pathway crosstalk by treating human donor islets and stem cell-derived islets (SC-islets) with TCDD +/- hypoxia and examined the changes in downstream targets of both AHR (e.g., CYP1A1) and HIF1 (e.g., HMOX1). SC-islets showed consistent crosstalk between AHR and HIF1 pathways; co-treatment of SC-islets with TCDD + hypoxia robustly suppressed the magnitude of CYP1A1 induction compared with TCDD treatment alone. In human islets, only 2 of 6 donors showing suppressed CYP1A1 induction following TCDD + hypoxia co-treatment. In both SC-islets and human donor islets we observed an unexpected hypoxia-mediated suppression of glucose-6-phosphate catalytic subunit 2 (G6PC2) expression. Our study shows AHR-HIF1 crosstalk occurs in both SC-islets and primary human donor islets, but the response of human islets varied between donors. In both models, the HIF1 pathway dominated over the AHR pathway during TCDD + hypoxia co-treatment. Our study is the first to examine whether AHR-HIF1 crosstalk occurs in islet cells and presents novel data on the impact of hypoxia on G6PC2 gene expression.

molecular biology↗

bioRxiv2018

Heavy metal sensitivities of gene deletion strains for ITT1 and RPS1A connect their activities to the expression of URE2, a key gene involved in metal detoxification in yeast

Heavy metal and metalloid contaminations are among the most concerning types of pollutant in the environment. Consequently, it is important to investigate the molecular mechanisms of cellular responses and detoxification pathways for these compounds in living organisms. To date, a number of genes have been linked to the detoxification process. The expression of these genes can be controlled at both transcriptional and translational levels. In bakers yeast, Saccharomyces cerevisiae, resistance to a wide range of toxic metals is regulated by glutathione S-transferases. Yeast URE2 encodes for a protein that has glutathione peroxidase activity and is homologous to mammalian glutathione S-transferases. The URE2 expression is critical to cell survival under heavy metal stress. Here, we report on the finding of two genes, ITT1, an inhibitor of translation termination, and RPS1A, a small ribosomal protein, that when deleted yeast cells exhibit similar metal sensitivity phenotypes to gene deletion strain for URE2. Neither of these genes were previously linked to metal toxicity. Our gene expression analysis illustrates that these two genes affect URE2 mRNA expression at the level of translation.\n\nSummary statementWe identified two yeast genes, ITT1 and RPS1A, that when deleted, results in yeast cells sensitivity to heavy metals and metalloids. Further investigation indicated that they influence the expression of URE2 gene, a key player in metal detoxification, by upregulating its translation. Our findings suggest that ITT1 and RPS1A play an indirect role in responding to toxic metal stress.

genomics↗