Discovery of novel anticancer therapies that target transcription factor Nrf2

 

The Nrf2 (NE-F2-related factor-2) transcription factor is a master regulator of redox homeostasis. Diverse environmental agents increase Nrf2 activity and it plays a fundamental role in cellular adaptation to oxidative stress. Specifically, Nrf2 controls the stress-inducible expression of a battery of genes for antioxidant proteins, drug-metabolising enzymes, drug-efflux pumps, and proteasome subunits, which in turn limit damage to macromolecules caused by reactive oxygen species and electrophiles.

Nrf2 is normally tightly controlled at the level of protein stability by the redox-sensitive ubiquitin ligase substrate adaptor Keap1 that targets the transcription factor for proteasomal degradation. However, Keap1 is frequently mutated in many types of tumours, resulting in up-regulation of Nrf2, causing increased cell proliferation and drug resistance. We have recently discovered that Nrf2 can be repressed by the ubiquitin ligase substrate adaptor β-TrCP in a glycogen synthase kinase-3 (GSK3)-dependent manner, and that activation of GSK3 restores sensitivity to anticancer drugs in cells that lack Keap1.

We are studying novel mechanisms, besides GSK3 activation, by which Nrf2 can be inhibited in tumours as a means of sensitizing them to chemotherapy and inhibiting cell proliferation. We focus on processes that decrease Nrf2 protein stability, block the recruitment of co-activators, or prevent the recruitment of Nrf2 to the promoters of its target genes. We also want to understand better how up-regulation of Nrf2 causes drug resistance and increased cell proliferation. Molecular biology, cell biology, pharmacology and biochemical methods, along with transgenic mouse models, will be employed to address these questions.

Supervisor: 
Professor John D Hayes
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