BBS Faculty Member - Keith Blackwell

Keith Blackwell

Department of Genetics

Joslin Diabetes Center
One Joslin Place, Rm. 655B
Boston, MA 02215
Tel: 617-309-2760
Fax: 617-309-3403
Email: keith.blackwell@joslin.harvard.edu
Lab Members: 4 postdoctoral fellows, 1 graduate student



My lab uses C. elegans to study how organisms defend against environmental and metabolic stresses, and how these stress defenses influence aging. Many of our projects are centered around the conserved transcription factor SKN-1/Nrf, which orchestrates a defensive response to oxidative stress and reactive toxins that is conserved among eukaryotes. SKN-1/Nrf regulates detoxification genes, promotes longevity, and is required for normal lifespan and oxidative stress resistance. Our more recent work has implicated SKN-1/Nrf in additional important stress defense functions, including maintenance of protein homeostasis.

In addition to elucidating how SKN-1/Nrf functions, we want to understand how it is regulated in response to stress and metabolic stimuli, and how it interfaces with other stress defense regulators. We have found that SKN-1/Nrf is inhibited directly by insulin/IGF-1 signaling (IIS), and contributes to the increased stress-resistance and longevity seen when IIS is reduced. We have also determined that SKN-1/Nrf responds to perturbations in protein synthesis, and is critical in relationships between growth signals, protein synthesis, and aging. This is particularly important in the context of the mTOR (mechanistic Target of Rapamycin) pathways, which are central to growth regulation. Both mTOR pathways (mTORC1 and mTORC2) regulate SKN-1/Nrf, and the lifespan extensions associated with suppression of either pathway depend upon SKN-1/Nrf. We are applying the advantages of
C. elegans to expand our understanding of how SKN-1/Nrf proteins function and promotes longevity, and how this and related stress defenses are regulated under normal and adverse conditions.



Last Update: 8/9/2013



Publications

For a complete listing of publications click here.

 


 

Tullet JMA, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK. (2008) Direct inhibition of the longevity promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell, 132, 1025-1038.

Oliveira RP, Porter Abate J, Dilks K, Landis J, Ashraf J, Murphy CT, Blackwell TK. (2009) Condition-adapted stress and longevity gene regulation by
Caenorhabditis elegans SKN-1/Nrf. Aging Cell, 8, 524-541.

Wang J, Robida-Stubbs S, Tullet JMA, Rual JF, Vidal M, Blackwell TK. (2010) RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet., 6, e1001048.

Li X, Matilainen O, Jin C, Glover-Cutter C, Holmberg CI, Blackwell TK. (2011) Specific SKN-1/Nrf stress responses to perturbations in translation elongation and proteasome activity. PLoS Genet., 7, e1002119.

Robida-Stubbs S, Glover-Cutter C, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, Sabatini DM, Blackwell TK. (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metabolism, 15, 713-724.



© 2013 by the President and Fellows of Harvard College