Tuesday, March 12, 2013 - 16:00 to 17:00
WTB Seminar Rooms
Albena T. Dinkova-Kostova
Division of Cancer Research, Medical Research Institute, University of Dundee
'Targeting the KEAP1/NRF2 pathway and the heat shock response for protection against carcinogenesis and chronic disease'
Tuesday 12 March at 1600 hours, WTB seminar rooms
If anyone would like to meet Dr.Dinkova-Kostova please let me know.
An elaborate network of highly inducible proteins protects aerobic cells against the cumulative damaging effects of reactive oxygen intermediates, toxic electrophiles, and misfolded proteins, the major causes of malignancy and chronic degenerative diseases. These cytoprotective proteins do not operate at their maximal capacity, but can be transcriptionally upregulated via the KEAP1/NRF2 pathway and the heat shock response by various chemical and phytochemical agents (inducers) all of which have sulfhydryl reactivity. At low concentrations, inducers react with critical cysteine residues of the sensor protein KEAP1, leading to activation of transcription factor NRF2, whereas at higher concentrations, they also activate heat shock factor 1 (HSF1). The interaction between KEAP1 and NRF2 follows a cycle whereby the protein complex sequentially adopts two distinct conformations: “open”, in which NRF2 interacts with one molecule of KEAP1, followed by “closed”, in which NRF2 binds to both members of the KEAP1 dimer. Inducers disrupt this cycle by causing accumulation of the complex in the “closed” conformation, without release of NRF2. Consequently, free KEAP1 is not regenerated, and newly-synthesized NRF2 is stabilized. This cyclic dynamic interaction allows rapid transcriptional responses to environmental changes and can accommodate multiple modes of regulation.