Photo of T. Keith Blackwell,  MD, PhD

T. Keith Blackwell, MD, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 309-2760
Fax: (617) 309-3403


keith.blackwell@joslin.harvard.edu

T. Keith Blackwell, MD, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Professor, Genetics, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

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 Our published and unpublished work has also determined that SKN-1/Nrf is regulated through different mechanisms by major pathways associated with growth or proliferation (insulin/IGF-1,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.

Publications

Powered by Harvard Catalyst
  • Ewald CY, Landis JN, Porter Abate J, Murphy CT, Blackwell TK. Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 2015; 519:97-101. PubMed
  • Moroz N, Carmona JJ, Anderson E, Hart AC, Sinclair DA, Blackwell TK. Dietary restriction involves NAD⁺ -dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 2014. PubMed
  • Mizunuma M, Neumann-Haefelin E, Moroz N, Li Y, Blackwell TK. mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 2014; 13:869-78. PubMed
  • Yoon JC, Ling AJ, Isik M, Lee DY, Steinbaugh MJ, Sack LM, Boduch AN, Blackwell TK, Sinclair DA, Elledge SJ. GLTSCR2/PICT1 links mitochondrial stress and Myc signaling. Proc Natl Acad Sci U S A 2014; 111:3781-6. PubMed
  • Ruf V, Holzem C, Peyman T, Walz G, Blackwell TK, Neumann-Haefelin E. TORC2 signaling antagonizes SKN-1 to induce C. elegans mesendodermal embryonic development. Dev Biol 2013; 384:214-27. PubMed
  • Glover-Cutter KM, Lin S, Blackwell TK. Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf. PLoS Genet. 2013; 9:e1003701. PubMed
  • Paek J, Lo JY, Narasimhan SD, Nguyen TN, Glover-Cutter K, Robida-Stubbs S, Suzuki T, Yamamoto M, Blackwell TK, Curran SP. Mitochondrial SKN-1/Nrf mediates a conserved starvation response. Cell Metab 2012; 16:526-37. PubMed
  • Mori MA, Raghavan P, Thomou T, Boucher J, Robida-Stubbs S, Macotela Y, Russell SJ, Kirkland JL, Blackwell TK, Kahn CR. Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab 2012; 16:336-47. PubMed
  • Wang J, Robida-Stubbs S, Tullet JM, Rual JF, Vidal M, Blackwell TK. RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet. 2010. PubMed
  • Abate JP, Blackwell TK. Life is short, if sweet. Cell Metab 2009; 10:338-9. PubMed
  • Oliveira RP, Abate JP, Dilks K, Landis J, Ashraf J, Murphy CT, Blackwell TK. Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf. Aging Cell 2009; 8:524-41. PubMed
  • Hammell CM,Lubin I,Boag PR,Blackwell TK,Ambros V. nhl-2 Modulates microRNA activity in Caenorhabditis elegans. Cell 2009; 136:926-38. PubMed
  • Olahova M,Taylor SR,Khazaipoul S,Wang J,Morgan BA,Matsumoto K,Blackwell TK,Veal EA. A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance. Proc Natl Acad Sci U S A 2008; 105:19839-44. PubMed
  • Blackwell TK,Walker AK. OMA-gosh, where's that TAF? Cell 2008; 135:18-20. PubMed
  • Boag PR,Atalay A,Robida S,Reinke V,Blackwell TK. Protection of specific maternal messenger RNAs by the P body protein CGH-1 (Dhh1/RCK) during Caenorhabditis elegans oogenesis. J Cell Biol 2008; 182:543-57. PubMed
  • Tullet JM,Hertweck M,An JH,Baker J,Hwang JY,Liu S,Oliveira RP,Baumeister R,Blackwell TK. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 2008; 132:1025-38. PubMed
  • Gartner A,Boag PR,Blackwell TK. Germline survival and apoptosis. WormBook 2008. PubMed
  • Lehtinen MK, Yuan Z, Boag PR, Yang Y, Vill. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 2006; 125:987-1001. PubMed
  • Gartner A, Boag RP, Blackwell TK. Germ cell survival and apoptosis 2008.
  • Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 2008; 132:915-6.
Hide