John Hayes

+44 (0)1382 383182
Professor of Molecular Carcinogenesis

Bio

Research

John Hayes received his undergraduate training (1972-1976) in the School of Biological Sciences at the University of Edinburgh, with final year of studies in Molecular Biology. He gained a PhD from the Medical School of the same university in 1980, awarded for investigation into bile acid-binding by glutathione S-transferase (GST) enzymes, which was undertaken in the laboratory of Professor Iain Percy-Robb. Upon completion of his PhD experimental work, he worked for 14 months as a NHS basic-grade Biochemist in the Department of Clinical Chemistry at the Western General Hospital in Edinburgh.

In 1981, Dr Hayes was appointed a Lecturer within the Department of Clinical Chemistry at the University of Edinburgh. Here, he focused research efforts on the biochemistry of the GST superfamily of drug-metabolising enzymes and the induction of certain members by chemoprotective drugs; this led to identification of previously unrecognised inducible GST isoenzymes several of which inactivated the fungal toxin aflatoxin B1. They subsequently demonstrated that upon treatment with chemoprotective agents, induction of these GST could suppress hepatocellular carcinoma caused by exposure to the mycotoxin. In 1991, he took sabbatical leave from the University of Edinburgh to work in the laboratory of Dr Cecil Pickett, Merck Frosst, Montreal, Canada, which was responsible for discovering the antioxidant response element (ARE) in the promoters of genes that can be induced by chemoprotective agents.

In October 1992, Dr Hayes moved as a Reader to the University of Dundee where he undertook research into regulation of drug-metabolising enzymes and identified the aldo-keto reductase 7A family (i.e. AKR7A) of genes, the founding member of which they discovered because it can be induced by chemoprotective drugs and catalyses inactivation of aflatoxin B1. In January 1997, the University of Dundee promoted him to a personal chair. Since then, his interest in the mechanisms by which gene expression is induced by cancer chemoprotective agents via ARE sequences has continued. This line of investigation led to the discovery that the NRF2 transcription factor (i.e. NF-E2 p45-related factor 2) regulates both basal and inducible expression of genes encoding GST, AKR, quinone reductase, glutathione biosynthetic enzymes and components of the thioredoxin antioxidant system, which collectively provide protection against oxidative stressors. Furthermore, his lab was the first to demonstrate that induction of genes regulated via ARE sequences requires stabilisation of NRF2 protein, which is inherently very unstable, through antagonism of the E3 cullin-3 RING ligase substrate adaptor KEAP1 (i.e. Kelch-like ECH-associated protein 1). Collectively, these findings, along with those of other research groups, have led to the recognition that the NRF2-KEAP1 pathway represents the master regulator of cellular antioxidant defences, and is therefore potentially involved in many degenerative diseases in which oxidative stress is implicated in their aetiology or progression. Interestingly, the Hayes laboratory subsequently discovered the existence of three independent stress sensors within KEAP1 that appear to have evolved separately: two of these are triggered by chemoprotective agents, whereas the third is triggered by hydrogen peroxide and various metal ions including Zn2+and Cd2+. Besides KEAP1, the Hayes lab also discovered a separate pathway that regulates NRF2 via ubiquitylation, which involves beta-TrCP (i.e. beta-transducin repeat-containing protein), and is dependent on prior phosphorylation of NRF2 by glycogen synthase kinase-3 GSK-3); this discovery is significant because through GSK-3, it provides a link between NRF2, redox homeostasis and intermediary metabolism.

Ongoing research in the Hayes laboratory has revealed that activation of NRF2 robustly stimulates endogenous antioxidant systems and, in the context of diabetes, non-alcoholic steatohepatitis and cirrhosis, suppresses inflammatory disease and liver fibrosis and blunts gluconeogenesis and lipid biosynthesis whilst promoting catabolism of fatty acids.

Prof Hayes has been a scientific advisor to the Medical Research Council and the Association for International Cancer Research. He has been a scientific advisor and served on the editorial boards of international scientific journals, including the Biochemical Journal, Carcinogenesis, Molecular & Cellular Biology, and the Journal of Pharmacology & Experimental Therapeutics.

The Hayes lab has published a total of 202 peer-reviewed original scientific papers and 28 solicited reviews/commentaries, most of which can be viewed through ResearchGate (www.researchgate.net/profile/John_Hayes9/).

Prof Hayes was elected a Fellow of the Royal Society of Edinburgh in May 2008, and a Fellow of the Society of Biology in September 2008.

Teaching

Prof Hayes contributes to the medical curriculum by providing a SSC module entitled “Antioxidants and Degenerative disease” for first-year MB ChB students in which evidence that dietary supplements improve redox signalling/oxidative stress and mitigate chronic diseases is evaluated. He also provides 10-week SSC research projects for third-year MB ChB students.

Hayes contributes to the BMSc course run for medical undergraduate students on diabetes by providing lectures/tutorials on “Hepatocyte redox status” and “Endoplasmic reticulum stress in non-alcoholic steatohepatitis”.

Hayes contributes to the science curriculum by running journal clubs and providing research projects for final-year undergraduate BSc students doing the Biological & Biomedical Science, the Cancer Biology, and the Cancer Pharmacology streams.

Hayes contributes to the MRes Cancer Biology course by providing research projects.

Publications

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
4/2019, Nature Reviews Drug Discovery
Research Output: Contribution To Journal > Review article

New insights into nuclear factor erythroid 2-related factors in toxicology and pharmacology
3/2019, Toxicology and Applied Pharmacology
Research Output: Contribution To Journal > Editorial

Zinc-binding triggers a conformational-switch in the cullin-3 substrate adaptor protein KEAP1 that controls transcription factor NRF2
12/2018, Toxicology and Applied Pharmacology
Research Output: Contribution To Journal > Article

Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)
3/2018, CMGH: Cellular and Molecular Gastroenterology and Hepatology
Research Output: Contribution To Journal > Article

A partnership with the proteasome : the destructive nature of GSK3
1/2018, Biochemical Pharmacology
Research Output: Contribution To Journal > Article

Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses
11/2017, Oncogene
Research Output: Contribution To Journal > Article

Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival
11/2017, Cancer Cell
Research Output: Contribution To Journal > Article

Epigenetic Control of NRF2-Directed Cellular Antioxidant Status in Dictating Life-Death Decisions
10/2017, Molecular Cell
Research Output: Contribution To Journal > Article

Corrigendum to "Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer"
8/2017, British Journal of Cancer
Research Output: Contribution To Journal > Article

Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice
7/2017, Carcinogenesis
Research Output: Contribution To Journal > Article

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