T. Keith Blackwell, MD, PhD
Professor, Department of Genetics, Harvard Medical School
DF/HCC Program AffiliationCancer Cell Biology
I have long-standing interests and expertise in developmental gene regulation, stress defenses, and aging. The central thread through most of my work as a principal investigator has been the stress defense and longevity transcription factor SKN-1/Nrf. My initial biochemical studies of SKN-1 eventually led me to convert my lab to a C. elegans group, and in recent years our research has coalesced around understanding its functions in aging, stress defense, and metabolism, and how it is regulated by stress and homeostatic signals. As a postdoc and new PI, I showed that SKN-1 is a DNA-binding transcription factor despite its unique predicted structure. My lab then determined that SKN-1 is the C. elegans ortholog of mammalian Nrf (NF-E2-related factor) proteins, and was the first group to implicate SKN-1/Nrf proteins in longevity in any organism. We showed that SKN-1/Nrf is not simply an acute stress response factor, but also modulates many biological processes under normal conditions. We also established that SKN-1/Nrf regulates distinct sets of genes and processes under different circumstances, and is regulated through a much more complex set of mechanisms than anticipated from mammalian studies. These findings revealed that SKN-1/Nrf has several important functions besides its well-known role in oxidative and xenobiotic stress resistance, including maintenance of proteasome expression and activity, a central role in the unfolded protein response (UPR), and control of lipid metabolism. Our published and unpublished work has also determined that SKN-1/Nrf is regulated through different mechanisms by major pathways associated with growth or proliferation (insulin/IGF-1, mTORC1, and mTORC2 signaling; germline stem cell proliferation), and in each case is critical in their effects on aging.
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