Deputy Head of Cancer Research Division /Professor of Chemical Biology
Understanding cellular stress responses related by transcription factors NRF2 and HSF1
Division of Cancer Research
Medical Research Institute
Jacqui Wood Cancer Centre
University of Dundee
Ninewells Hospital and Medical School
+(44) 01382 383386
Albena T. Dinkova-Kostova obtained her PhD in Biochemistry from Washington State University. Her doctoral work was on the purification and characterization of enzymes of the phenylpropanoid pathway. During that time she became intrigued by the fact that phenylpropanoids, some of which (podophyllotoxin and the semi-synthetic etoposide and tenoposide) are used in cancer chemotherapy; others (nordihydroguaiaretic acid) are potent antioxidants, are also inducers of anticarcinogenic enzymes. She joined the laboratory of Paul Talalay (Johns Hopkins University) where she became interested in chemoprevention by chemical and dietary induction of cytoprotective proteins.
In 2007 Albena joined the Medical Research Institute, University of Dundee, Scotland as a Lecturer and Research Councils UK Academic Fellow. Her work on the mechanism of induction of cytoprotective proteins (through the Keap1/Nrf2 pathway) and the chemistry of inducers has been published in Biochemistry, Cancer Prevention Research, Chemical Research in Toxicology, Chemistry & Biology, Journal of Biological Chemistry, Journal of Medicinal Chemistry, Methods of Enzymology, and the Proceedings of the National Academy of Sciences USA. It has been highlighted in commentaries and attracted more than 5000 citations. She is the recipient of the 2011 Arthur C. Neish Young Investigator Award of the Phytochemical Society of North America.
The steady increase in the number of new cancer cases diagnosed each year and the modest success in cancer treatment highlight the urgent need for the development of strategies for prevention. It is important to understand that the disease cancer is the process of carcinogenesis itself that begins many years, often decades, before any clinical symptoms become apparent. Protection against cancer in animal models can be accomplished by induction of the Keap1/Nrf2 pathway which controls the gene expression of numerous enzymes (e.g., glutathione S-transferases, epoxide hydrolase, quinone reductase 1, heme oxygenase 1) that catalyze versatile reactions collectively leading to detoxification of electrophiles and oxidants. The expression of Nrf2-dependent genes can be elevated by a wide variety of pharmacological agents termed “inducers”, some of which are present in the human diet. Inducers react with specific cysteine residues of the sensor protein Keap1, thereby allowing transcription factor Nrf2 to translocate to the nucleus and activate transcription. The discrete events in the regulation of the Keap1/Nrf2 pathway and the mechanism of action of Nrf2 inducers are a major objective of our research. We are also investigating the regulation of the heat shock response, another cellular cytoprotective pathway, and the ability of small molecules which can inhibit Hsp90 to interfere with cancer cell proliferation.
In addition to biochemical studies in various in vitro and cellular systems, we also employ in vivo models with a focus on models of UV radiation-induced skin carcinogenesis. The knowledge obtained from these models will allow the design of clinical trials to determine the effectiveness of Nrf2 inducers in preventing the development of skin cancers in high-risk populations, such as solid organ transplant recipients who are at nearly 100-fold increased risk for skin cancer development compared to the general population.
The heat shock response and the Keap1/Nrf2 pathway are highly inducible essential defense systems that allow the cell to adapt and survive under various conditions of stress by regulating the expression of elaborate networks of several hundred genes with versatile cytoprotective functions. Under homeostatic conditions, they do not operate at their maximal capacity, but are induced by numerous chemical and phytochemical agents, termed inducers. At low concentrations (top half of the image), inducers (yellow stars) bind to cysteine residues of the protein sensor Keap1 (blue). Consequently, Keap1 loses its ability to target transcription factor Nrf2 (purple) for ubiquitination via Cul3 (pink)-dependent E3 ubiquitin ligase, preventing subsequent proteosomal degradation of Nrf2 and allowing its accumulation and nuclear translocation to induce expression of Nrf2-target genes. At high concentrations (bottom half of the image), in addition to activating the Keap1/Nrf2 pathway, inducers also activate the heat shock response by chemically reacting with transcription factor Hsf1 (red), or its negative regulator, Hsp90 (cyan). As a result, Hsf1 undergoes post-translational modifications, dissociates from the protein complex, trimerizes, translocates to the nucleus, and induces expression of Hsf1-target genes. Image created by Rumen Kostov (Medical Research Institute).
- Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014 Apr;39(4):199-218. Epub 2014 Mar 16.
- Baird L, Swift S, Llères D, Dinkova-Kostova AT. Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol Adv. 2014 Mar 25.
- Ludtmann MH, Angelova PR, Zhang Y, Abramov AY, Dinkova-Kostova AT. Nrf2 impacts the efficiency of mitochondrial fatty acid oxidation. Biochem J. 2013 (in press).
- Zhang Y, Dayalan Naidu S, Samarasinghe K, Van Hecke GC, Pheely A, Boronina TN, Cole RN, Benjamin IJ, Cole PA, Ahn YH, Dinkova-Kostova AT. Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation. Br J Cancer. 2013 (in press).
- Baird L, Llères D, Swift S, Dinkova-Kostova AT. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci USA. 2013; 110: 15259-15264.
- Kalra S, Knatko EV, Zhang Y, Honda T, Yamamoto M, Dinkova-Kostova AT. Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): Implications for protection against UV radiation during thiopurine therapy. Cancer Prev Res (Phila). 2012; 5: 973-981.
- Kalra S, Zhang Y, Knatko EV, Finlayson S, Yamamoto M, Dinkova-Kostova AT. Oral azathioprine leads to higher incorporation of 6-thioguanine in DNA of skin than liver: The protective role of the Keap1/Nrf2/ARE pathway. Cancer Prev Res (Phila). 2011; 4: 1665-1674.
- Zhang Y, Ahn YH, Benjamin IJ, Honda T, Hicks R, Calabrese V, Cole PA, Dinkova-Kostova AT. HSF1-dependent upregulation of Hsp70 by sulfhydryl-reactive inducers of the KEAP1/NRF2/ARE pathway. Chem Biol. 2011; 18: 1355-1361.
- Ahn YH, Hwang Y, Liu H, Wang XJ, Zhang Y, Stephenson KK, Boronina TN, Cole RN, Dinkova-Kostova AT, Talalay P, Cole PA. Electrophilic tuning of the chemoprotective natural product sulforaphane. Proc Natl Acad Sci USA. 2010; 107: 9590-9595.
- Dinkova-Kostova AT, Talalay P, Sharkey J, Zhang Y, Holtzclaw WD, Wang XJ, David E, Schiavoni KH, Finlayson S, Mierke DF, Honda T. An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1. J Biol Chem. 2010; 285: 33747-33755.
- Wang XJ, Hayes JD, Higgins LG, Wolf CR, Dinkova-Kostova AT. Activation of the Nrf2 signalling pathway by copper-mediated redox cycling of para- and ortho-hydroquinones. Chem Biol. 2010; 17: 75-85.
- Liu H, Dinkova-Kostova AT, Talalay P. Coordinate regulation of enzyme markers for inflammation, and for protection against oxidants and electrophiles. Proc Natl Acad Sci USA 2008; 105: 15926-15931.
- Kerns ML, DePianto D, Dinkova-Kostova AT, Talalay P, Coulombe PA. Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in Epidermolysis Bullosa Simplex. Proc Natl Acad Sci USA 2007; 104: 14460-14465.
- Talalay P, Fahey J, Healy ZR, Wehage SL, Benedict AL, Min C, Dinkova-Kostova AT. Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci USA 2007; 104: 17500-17505.
Parts of Molecular Oncology Module for the 4th-year Life Sciences students, College of Life Sciences, University of Dundee, Dundee;
Parts of Cellular Stress Responses Module for the 4th-year Pharmacology students, College of Medicine, Dentistry and Nursing, University of Dundee, Dundee;
Supervision of final year degree projects, University of Dundee
Parts of Nutrition and Chronic Disease Prevention course, Johns Hopkins University, Baltimore, MD, USA;
Parts of M.S. course in Nutritional Medicine, Module 3: “Antioxidants, Phytoprotectants and Disease”, University of Surrey, Guildford
Previous: Liam Baird “Single Cell Analysis of Keap1-Nrf2 Dynamics” 2012
Current: Sharadha Dayalan Naidu “The Spatiotemporal Regulation of Heat Shock Factor 1 in Single Live Cells”
- 2009 “Role and regulation of phase 2 genes in protection against oxidative and electrophilic stress”, Second Tiselius Symposium, Uppsala, Sweden
- 2010 “Chemoprotection against oxidants and electrophiles: The lessons learned and the expectations from targeting the Keap1/Nrf2/ARE pathway”, MRC Mitochondrial Biology Unit, Cambridge, United Kingdom
- 2010 “Induction of the Keap1/Nrf2/ARE pathway by oxidizable diphenols”, Biological Reactive Intermediates VIII Conference, Barcelona, Spain
- 2011 “The role of the Keap1/Nrf2/ARE pathway in protection against UV radiation”, 14thCongress of the European Society for Photobiology, Geneva, Switzerland
- 2011 “Direct and indirect antioxidant properties of inducers of the Keap1/Nrf2/ARE pathway”, 10th Indo-Italian Workshop on Chemistry and Biology of Antioxidants, Rome Italy
- 2011 “A novel role for sulfhydryl-reactive activators of transcription factor NRF2: HSF1-dependent upregulation of Hsp70”, 50th Anniversary Meeting of the Phytochemical Society of North America, Hawai’i, USA
- 2011 “Targeting the Keap1/Nrf2/ARE pathway for chemoprotection”, Institute of Neurology, University College London, London, United Kingdom
- 2012 “The spatiotemporal regulation of the Keap1/Nrf2/ARE pathway”, 7th International Congress on Heme Oxygenases and Related Enzymes, Edinburgh, United Kingdom
- 2012 “Targeting the Keap1/Nrf2/ARE pathway and the heat shock response for chemoprotection”, session “Small Molecule Modulation of Cell Stress Response Pathways: From Chemical Design to Clinical Opportunities”, 244th American Chemical Society National Meeting and Exposition, Philadelphia, Pennsylvania, USA
- 2013 “Targeting the KEAP1/NRF2 pathway and the heat shock response for prevention of chronic disease”, Institute for Food Research, Norwich Research Park, Norwich, United Kingdom
- 2013 “Induction of cytoprotective responses by plant isothiocyanates and synthetic analogues”, International conference on Natural Products Utilization: from Plants to Pharmacy Shelf, Bansko, Bulgaria
- 2013 “Chemoprevention against cancer by isothiocyanates”, XVII Gliwice Scientific Meetings, Gliwice, Poland
Liam Baird obtained his PhD in 2012 and is currently a postdoctoral researcher in the laboratory of Masayuki Yamamoto, Tohoku University, Sendai, Japan