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Sci. Signal., 9 March 2010
Vol. 3, Issue 112, p. re3
[DOI: 10.1126/scisignal.3112re3]


Stress-Activated Cap'n'collar Transcription Factors in Aging and Human Disease

Gerasimos P. Sykiotis1,2* and Dirk Bohmann1

1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
2 Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract: Cap’n’collar (Cnc) transcription factors are conserved in metazoans and have important developmental and homeostatic functions. The vertebrate Nrf1, Nrf2, and Nrf3; the Caenorhabditis elegans SKN-1; and the Drosophila CncC comprise a subgroup of Cnc factors that mediate adaptive responses to cellular stress. The most studied stress-activated Cnc factor is Nrf2, which orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In rodent models, signaling by Nrf2 defends against oxidative stress and aging-associated disorders, such as neurodegeneration, respiratory diseases, and cancer. In humans, polymorphisms that decrease Nrf2 abundance have been associated with various pathologies of the skin, respiratory system, and digestive tract. In addition to preventing disease in rodents and humans, Cnc factors have life-span–extending and anti-aging functions in invertebrates. However, despite the pro-longevity and antioxidant roles of stress-activated Cnc factors, their activity paradoxically declines in aging model organisms and in humans suffering from progressive respiratory disease or neurodegeneration. We review the roles and regulation of stress-activated Cnc factors across species, present all reported instances in which their activity is paradoxically decreased in aging and disease, and discuss the possibility that the pharmacological restoration of Nrf2 signaling may be useful in the prevention and treatment of age-related diseases.

* Corresponding author. E-mail: gerasimos_sykiotis{at}

Citation: G. P. Sykiotis, D. Bohmann, Stress-Activated Cap'n'collar Transcription Factors in Aging and Human Disease. Sci. Signal. 3, re3 (2010).

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T. Wu, F. Zhao, B. Gao, C. Tan, N. Yagishita, T. Nakajima, P. K. Wong, E. Chapman, D. Fang, and D. D. Zhang (2014)
Genes & Dev. 28, 708-722
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. C. Lessard, S. Pina-Paz, J. D. Rotty, R. P. Hickerson, R. L. Kaspar, A. Balmain, and P. A. Coulombe (2013)
PNAS 110, 19537-19542
   Abstract »    Full Text »    PDF »
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C. K. Leung, Y. Wang, A. Deonarine, L. Tang, S. Prasse, and K. P. Choe (2013)
Mol. Cell. Biol. 33, 3524-3537
   Abstract »    Full Text »    PDF »
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Y. Tsuchiya, H. Taniguchi, Y. Ito, T. Morita, M. R. Karim, N. Ohtake, K. Fukagai, T. Ito, S. Okamuro, S.-i. Iemura, et al. (2013)
Mol. Cell. Biol. 33, 3461-3472
   Abstract »    Full Text »    PDF »
Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy.
M. A. Aminzadeh, S. B. Nicholas, K. C. Norris, and N. D. Vaziri (2013)
Nephrol. Dial. Transplant. 28, 2038-2045
   Abstract »    Full Text »    PDF »
Molecular Biology of Atherosclerosis.
P. N. Hopkins (2013)
Physiol Rev 93, 1317-1542
   Abstract »    Full Text »    PDF »
Upregulation of Nrf2 expression by human cytomegalovirus infection protects host cells from oxidative stress.
J. Lee, K. Koh, Y.-E. Kim, J.-H. Ahn, and S. Kim (2013)
J. Gen. Virol. 94, 1658-1668
   Abstract »    Full Text »    PDF »
Bach2 maintains T cells in a naive state by suppressing effector memory-related genes.
S.-i. Tsukumo, M. Unno, A. Muto, A. Takeuchi, K. Kometani, T. Kurosaki, K. Igarashi, and T. Saito (2013)
PNAS 110, 10735-10740
   Abstract »    Full Text »    PDF »
Differential regulation of proteasome functionality in reproductive vs. somatic tissues of Drosophila during aging or oxidative stress.
E. N. Tsakiri, G. P. Sykiotis, I. S. Papassideri, V. G. Gorgoulis, D. Bohmann, and I. P. Trougakos (2013)
FASEB J 27, 2407-2420
   Abstract »    Full Text »    PDF »
Proteomic Analysis of Ubiquitin Ligase KEAP1 Reveals Associated Proteins That Inhibit NRF2 Ubiquitination.
B. E. Hast, D. Goldfarb, K. M. Mulvaney, M. A. Hast, P. F. Siesser, F. Yan, D. N. Hayes, and M. B. Major (2013)
Cancer Res. 73, 2199-2210
   Abstract »    Full Text »    PDF »
A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative stress adaptation in mammals, Caenorhabditis elegans and Drosophila melanogaster.
A. M. Pickering, T. A. Staab, J. Tower, D. Sieburth, and K. J. A. Davies (2013)
J. Exp. Biol. 216, 543-553
   Abstract »    Full Text »    PDF »
The transcription factor NF-E2-related Factor 2 (Nrf2): a protooncogene?.
P. Shelton and A. K. Jaiswal (2013)
FASEB J 27, 414-423
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p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition.
S. K. Radhakrishnan, W. den Besten, and R. J. Deshaies (2013)
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Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency.
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F. Lieder, F. Reisen, T. Geppert, G. Sollberger, H.-D. Beer, U. auf dem Keller, M. Schafer, M. Detmar, G. Schneider, and S. Werner (2012)
J. Biol. Chem. 287, 33001-33013
   Abstract »    Full Text »    PDF »
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A. Y.-L. So, Y. Garcia-Flores, A. Minisandram, A. Martin, K. Taganov, M. Boldin, and D. Baltimore (2012)
Blood 120, 2428-2437
   Abstract »    Full Text »    PDF »
Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha.
B. N. Chorley, M. R. Campbell, X. Wang, M. Karaca, D. Sambandan, F. Bangura, P. Xue, J. Pi, S. R. Kleeberger, and D. A. Bell (2012)
Nucleic Acids Res. 40, 7416-7429
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Y. Hirotsu, N. Hataya, F. Katsuoka, and M. Yamamoto (2012)
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I. Lastres-Becker, A. Ulusoy, N. G. Innamorato, G. Sahin, A. Rabano, D. Kirik, and A. Cuadrado (2012)
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