Nrf2 regulation by Hsp90, oxidation, and in breast cancer
Abstract
To cope with the dynamic range of stressful stimuli that a cell experiences within its lifetime, a host of adaptive cell survival and cell stress response pathways have evolved. The antioxidant and heat shock responses are two key cell stress response pathways primarily involved in the detoxification and elimination of oxidative stress and the maintenance of protein integrity, respectively. Traditionally, these responses are regarded and studied as two independent pathways. In this exploratory work, we hypothesize that oxidative damage to Nrf2 and Keap1 and their interactions with Hsp90 alter their function within the cellular antioxidant stress response. By establishing and characterizing a novel yeast model for human Nrf2, the transcriptional master regulator of the antioxidant response, a previously unexplored interaction was found between Nrf2 and the major heat shock response protein, Hsp90. Further investigation into this interaction using mammalian and breast cancer cells reveals the co-involvement of these proteins in key aspects of protein oxidation, protein misfolding, and cellular responses to cancer therapy. Additionally, Nrf2 and its regulating protein Keap1 were observed to misfold and form protein inclusions upon exposure to oxidative stress, which might implicate a previously unknown mechanism of Nrf2 regulation by inclusion formation. These findings suggest that investigating the antioxidant and heat shock responses in parallel may provide an additional layer of knowledge that is relevant to both basic science and clinical research.