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John D Hayes, FRSE, FIBiol
Professor of Molecular Carcinogenesis
Molecular Mechanisms of Cancer Chemoprevention and Control of Antioxidant Pathways
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E-mail: j.d.hayes@dundee.ac.uk Tel. 01382 632788
The fact that more than 80% of cancer cases are attributable to environmental factors suggests that many forms of malignant disease are preventable. Epidemiological studies indicate that cancer susceptibility is influenced significantly by diet. This probably entails either dietary consumption of carcinogens that exceed the detoxification defences of the host, or consumption of diets that contain insufficient amounts of anticarcinogens, otherwise called cancer chemopreventive agents.
The underlying molecular mechanisms by which diet influences the development of cancer are poorly understood. A large number of naturally occurring chemicals, as well as synthetic food additives, have been shown to protect against carcinogenesis. Indoles and isothiocyanates (found in cruciferous vegetables), flavonoids (in citrus fruit), coumarins, (found in legumes) and organosulphurs (in garlic and onion) are some of the phytochemicals that can prevent chemical carcinogenesis. These compounds appear to confer resistance against carcinogenesis through their ability to generate redox stress that, in turn, stimulates increased expression of protective antioxidant and detoxication proteins in specific organs of the host. Such cytoprotective enzymes include heme oxygenase 1, glutamate cysteine ligase, glutathione S-transferase, NAD(P)H:quinone oxidoreductase 1, aldo-keto reductase and UGT-glucuronosyl transferase [1-4].
One of the major pathways by which phytochemicals increase the expression of antioxidant and detoxication enzymes in mammalian cells involves the cis-acting antioxidant responsive element found in the promoters of inducible genes [5]. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the cap‘n’collar family of basic-region leucine zipper transcription factors, mediates induction of ARE-driven gene expression [5]. The Nrf2 transcription factor is required to form heterodimers with small Maf proteins (MafF, MafG or MafK) before it can bind the ARE. Under basal conditions, Nrf2 is highly unstable and is targeted for proteasomal degradation by Keap1, an adaptor protein for a Cul3-based ubiquitin ligase (see the Figure). Activation of Nrf2 by oxidative stress involves inactivation of Keap1, an event that causes the half-life of Nrf2 to increase about 5-fold and the factor to accumulate in the nucleus [6, 7].
In an attempt to identify mechanisms that are important in chemoprevention we have begun to examine the role of Nrf2 and Keap1 in regulating expression of antioxidant and detoxication proteins. Gene knockout models, RNAi, and transfection of Nrf2/Keap1 mutants into cell lines, are being used to profile downstream enzymes regulated by the factors. This work will not only define the ARE gene battery, but will allow the role of different transcription factors in regulating expression of antioxidant genes to be determined. The principal current objectives entail identification of the phenotypic consequences of either loss of Nrf2 or its constitutive activation in terms of susceptibility to damage and/or apoptosis following exposure to harmful agents. To date we have demonstrated that Nrf2 mediates the antioxidant effects of broccoli seeds [8], but further work is required to determine how individual phytochemicals activate Nrf2. In the longer term, the aim of this programme of work is to provide a molecular understanding of how dietary manipulation can prevent the development of cancer and also other degenerative diseases where oxidative stress is implicated in their aetiology.
Current grant support from AICR, BBSRC, MRC and WCRF.
References
McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C & Hayes JD (2001) The cap‘n’collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res. 61: 3299-3307
Chanas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, Yamamoto M & Hayes JD (2002) Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem. J. 365: 405-416
Nioi P & Hayes JD (2004) Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the Arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutation Res. 555: 149-171
Hayes JD, Flanagan JU & Jowsey IR (2005) Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 45: 51-88
Nioi P, McMahon M, Itoh K, Yamamoto M & Hayes JD (2003) Identification of a novel Nrf2-regulated antioxidant response element in the mouse NAD(P)H:quinone oxidoreductase 1 gene; reassessment of the ARE consensus sequence. Biochem. J. 374: 337-348
McMahon M, Itoh K, Yamamoto M & Hayes JD (2003) Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J. Biol. Chem. 278: 21592-21600
McMahon M, Thomas N, Itoh K, Yamamoto M & Hayes JD (2004) Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J. Biol. Chem. 279: 31556-31567
McWalter GK, Higgins LG, McLellan LI, Henderson CJ, Song L, Thornalley PJ, Itoh K, Yamamoto M & Hayes JD (2004) Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J. Nutr. 134: 3499S-3506S
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