D Hayes

Biography

Professor Hayes initially trained between 1972 and 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 properties of hepatic glutathione S-transferases. In 1981, he was appointed a Lecturer within the University Department of Clinical Chemistry at Edinburgh. Here, he focused attention on the enzymology and protein chemistry of the glutathione S-transferase (GST) superfamily in rodents and human, and became particularly interested in the contribution of inducible class Alpha GST to chemoprevention against the liver carcinogen aflatoxin B1 and the contribution made by overexpressed GST in tumours to acquired resistance to anticancer drugs. In 1991, he took sabbatical leave from the University of Edinburgh to work in the laboratory of Dr Cecil B. Pickett, in the Department of Molecular Biology, Merck Frosst, Montreal, Canada, which was responsible for discovering the antioxidant response element (ARE) in the promoters of genes for inducible GST and for NAD(P)H:quinone oxidoreductase 1 (NQO1). Upon return from sabbatical, the University of Edinburgh promoted Dr Hayes to a Readership in Clinical Biochemistry.  In October 1992, Dr Hayes moved as a Reader to the University of Dundee to help Prof C. Roland Wolf set up the Biomedical Research Centre in the Medical School. In this environment, he focused more on the molecular biology and regulation of detoxication enzymes and identified a new family of inducible aldo-keto reductases (AKR) that metabolises a dialdehydic form of aflatoxin B1 and quinones. In January 1997, the University of Dundee promoted him to a personal chair. Since then, his interest in the role of the ARE in directing induction of detoxication genes has continued, and he has collaborated with Prof Masayuki Yamamoto (Tohoku, Japan) to demonstrate that the Nrf2 transcription factor regulates both basal and inducible expression of GST, AKR, NQO1 and glutathione biosynthetic enzymes. More recently, Prof Hayes’ lab has shown that control of the ARE-gene battery critically depends on the stability of Nrf2 protein, and inhibition of the ubiquitin ligase adaptor Keap1 blocks turn-over of the transcription factor. Workers in the Hayes laboratory were the first to show that Nrf2 stability is controlled by Keap1, and have more recently demonstrated the existence of three independent stress sensors in Keap1 that evolved separately.  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.

Research Interest

Mechanisms of regulation of transcription factor Nrf2 and their relevance to chemoprotection and novel cancer treatment therapies.  The Nrf2 transcription factor is a master regulator of redox homeostasis. It is activated by diverse environmental agents and plays a fundamental role in cellular adaptation to oxidative stress and electrophilic chemicals. Specifically, Nrf2 controls the stress-inducible expression of a battery of genes for antioxidant proteins, NADPH regeneration enzymes, drug-metabolising enzymes, drug efflux pumps, and proteasome subunits. In normal cells, activation of Nrf2 has strong anti-inflammatory effects and limits damage to macromolecules caused by reactive oxygen species and electrophiles. Indeed, many cancer chemopreventive agents that protect against DNA damage by carcinogens do so by activating Nrf2 and inducing its target genes. On the other hand, Nrf2 is frequently constitutively activated in cancer cells, and this is associated with increased drug resistance and a higher rate of proliferation of such cells.  Given the involvement of Nrf2 in both the prevention of carcinogenesis in normal cells and in the promotion of tumourigenesis in cells in which cancer has been initiated, there is an obvious need to understand the mechanisms by which it is regulated. Nrf2 is principally controlled at the protein level through ubiquitylation, which targets the transcription factor for proteasomal degradation. To date, the ubiquitin ligase substrate adaptors Keap1 and beta-TrCP have been found to play central roles in repressing Nrf2 through their involvement in CRL(Keap1) and SCF(beta-TrCP) ubiquitin ligases: Keap1 regulates Nrf2 in an oxidative stress-sensitive fashion; beta-TrCP regulates Nrf2 in a glycogen synthase kinase-3 (GSK3)-dependent manner that also integrates several signal transduction pathways. Other mechanisms by which Nrf2 is regulated entail control of its subcellular localization.  The Hayes laboratory is particularly interested in how Keap1 and the beta-TrCP-GSK3 pathway sense stressors and whether such knowledge can be used to identify more potent chemopreventive agents that activate Nrf2 efficiently in normal cells, or to either discover small molecule inhibitors that repress Nrf2 in cancer cells. We have discovered that Keap1 contains three independent stress sensors and are characterizing them to determine how they are triggered, and how they might recover from modification by various stressors. Also, we are currently investigating the mechanisms by which GSK3 allows ubiquitylation of Nrf2 by SCF(beta-TrCP) and identify the signal transduction pathways that regulate phosphorylation of Nrf2 by GSK3. Biochemical, molecular biology and cell biology methods, along with transgenic mouse models, will be employed to address these questions.