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 Our published and unpublished work has also determined that SKN-1/Nrf is regulated through different mechanisms by major pathways associated with growth or proliferation (insulin/IGF-1,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

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  • 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
  • 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
  • An JH, Vranas K, Lucke M, Inoue H, Hisamoto N, Matsumoto K, Blackwell TK. Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proc Natl Acad Sci U S A 2005; 102:16275-80. PubMed
  • Boag PR, Nakamura A, Blackwell TK. A conserved RNA-protein complex component involved in physiological germline apoptosis regulation in C. elegans. Development 2005; 132:4975-86. PubMed
  • Inoue H, Hisamoto N, An JH, Oliveira RP, Nishida E, Blackwell TK, Matsumoto K. The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response. Genes Dev 2005; 19:2278-83. PubMed
  • Navarro RE, Blackwell TK. Requirement for P granules and meiosis for accumulation of the germline RNA helicase CGH-1. Genesis 2005; 42:172-80. PubMed
  • Wang JC, Walker A, Blackwell TK, Yamamoto KR. The Caenorhabditis elegans ortholog of TRAP240, CeTRAP240/let-19, selectively modulates gene expression and is essential for embryogenesis. J Biol Chem 2004; 279:29270-7. PubMed
  • Walker AK, Shi Y, Blackwell TK. An extensive requirement for transcription factor IID-specific TAF-1 in Caenorhabditis elegans embryonic transcription. J Biol Chem 2004; 279:15339-47. PubMed
  • Stoecklin G, Stubbs T, Kedersha N, Wax S, Rigby WF, Blackwell TK, Anderson P. MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J 2004; 23:1313-1324. PubMed
  • Blackwell TK. Germ cells: finding programs of mass repression. Curr Biol 2004; 14:R229-30. PubMed
  • Blackwell TK, Walker AK. Transcription elongation: TLKing to chromatin? Curr Biol 2003; 13:R915-6. PubMed
  • Shi Y, Blackwell TK. A two-tiered transcription regulation mechanism that protects germ cell identity. Mol Cell 2003; 12:1062-4. PubMed
  • An JH, Blackwell TK. SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 2003; 17:1882-93. PubMed
  • Takagi T, Walker AK, Sawa C, Diehn F, Takase Y, Blackwell TK, Buratowski S. The Caenorhabditis elegans mRNA 5'-capping enzyme. In vitro and in vivo characterization. J Biol Chem 2003; 278:14174-84. PubMed
  • Zhang F, Barboric M, Blackwell TK, Peterlin BM. A model of repression: CTD analogs and PIE-1 inhibit transcriptional elongation by P-TEFb. Genes Dev 2003; 17:748-58. PubMed
  • Walker AK, Blackwell TK. A broad but restricted requirement for TAF-5 (human TAFII100) for embryonic transcription in Caenorhabditis elegans. J Biol Chem 2002; 278:6181-6. PubMed
  • Shim EY, Walker AK, Blackwell TK. Broad requirement for the mediator subunit RGR-1 for transcription in the Caenorhabditis elegans embryo. J Biol Chem 2002; 277:30413-6. PubMed
  • Shim EY, Walker AK, Shi Y, Blackwell TK. CDK-9/cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev 2002; 16:2135-46. PubMed
  • Johnson BA, Blackwell TK. Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNFalpha through distinct pathways. Oncogene 2002; 21:4237-46. PubMed
  • Johnson BA, Stehn JR, Yaffe MB, Blackwell TK. Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms. J Biol Chem 2002; 277:18029-36. PubMed
  • Blackwell TK, Walker AK. Getting the right dose of repression. Genes Dev 2002; 16:769-72. PubMed
  • Walker AK, Rothman JH, Shi Y, Blackwell TK. Distinct requirements for C.elegans TAF(II)s in early embryonic transcription. EMBO J 2001; 20:5269-79. PubMed
  • Navarro RE, Shim EY, Kohara Y, Singson A, Blackwell TK. cgh-1, a conserved predicted RNA helicase required for gametogenesis and protection from physiological germline apoptosis in C. elegans. Development 2001; 128:3221-32. PubMed
  • Walker AK, See R, Batchelder C, Kophengnavong T, Gronniger JT, Shi Y, Blackwell TK. A conserved transcription motif suggesting functional parallels between Caenorhabditis elegans SKN-1 and Cap'n'Collar-related basic leucine zipper proteins. J Biol Chem 2000; 275:22166-71. PubMed
  • Johnson BA, Geha M, Blackwell TK. Similar but distinct effects of the tristetraprolin/TIS11 immediate-early proteins on cell survival. Oncogene 2000; 19:1657-64. PubMed
  • Gartner A, Boag RP, Blackwell TK. Germ cell survival and apoptosis 2008.
  • Kophengnavong T, Michnowicz JE, Blackwell TK. Establishment of distinct MyoD, E2A, and twist DNA binding specificities by different basic region-DNA conformations. Mol Cell Biol 1999; 20:261-72. 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; 132:915-6.
  • Kophengnavong T, Carroll AS, Blackwell TK. The SKN-1 amino-terminal arm is a DNA specificity segment. Mol Cell Biol 1999; 19:3039-50. PubMed
  • De J, Lai WS, Thorn JM, Goldsworthy SM, Liu X, Blackwell TK, Blackshear PJ. Identification of four CCCH zinc finger proteins in Xenopus, including a novel vertebrate protein with four zinc fingers and severely restricted expression. Gene 1999; 228:133-45. PubMed
  • Batchelder C, Dunn MA, Choy B, Suh Y, Cassie C, Shim EY, Shin TH, Mello C, Seydoux G, Blackwell TK. Transcriptional repression by the Caenorhabditis elegans germ-line protein PIE-1. Genes Dev 1999; 13:202-12. PubMed
  • Carroll AS, Gilbert DE, Liu X, Cheung JW, Michnowicz JE, Wagner G, Ellenberger TE, Blackwell TK. SKN-1 domain folding and basic region monomer stabilization upon DNA binding. Genes Dev 1997; 11:2227-38. PubMed
  • Huang J, Blackwell TK, Kedes L, Weintraub H. Differences between MyoD DNA binding and activation site requirements revealed by functional random sequence selection. Mol Cell Biol 1996; 16:3893-900. PubMed
  • Blackwell TK. Selection of protein binding sites from random nucleic acid sequences. Methods Enzymol 1995; 254:604-18. PubMed
  • Blackwell TK, Bowerman B, Priess JR, Weintraub H. Formation of a monomeric DNA binding domain by Skn-1 bZIP and homeodomain elements. Science 1994; 266:621-8. PubMed
  • Blackwell TK, Huang J, Ma A, Kretzner L, Alt FW, Eisenman RN, Weintraub H. Binding of myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol 1993; 13:5216-24. PubMed
  • Blackwell TK, Weintraub H. Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection. Science 1990; 250:1104-10. PubMed
  • Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science 1990; 250:1149-51. PubMed
  • Blackwell TK, Moore MW, Yancopoulos GD, Suh H, Lutzker S, Selsing E, Alt FW. Recombination between immunoglobulin variable region gene segments is enhanced by transcription. Nature 1986; 324:585-9. PubMed
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