Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

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

REVIEWS

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.

Gloss: Cap’n’collar (Cnc) proteins form a family of basic leucine zipper transcription factors. Some Cnc factors have important functions in development, whereas others are critical for maintaining homeostasis in the face of environmental stresses. The "electrophile counterattack" is a conserved cellular response to oxidative stressors and electrophilic xenobiotics. In this adaptive process, Cnc factors transcriptionally activate protective genes through antioxidant response elements (AREs) in their regulatory sequences. In vertebrates, the electrophile counterattack is largely mediated by Nrf2. By defending animals against oxidative stress, Nrf2 prevents DNA and protein damage and protects against the development of cancer and many other oxidative stress-related disorders, including respiratory and neurodegenerative diseases. In animal models of disease, pharmacological activation of Nrf2 can prevent cancer and other pathologies linked to oxidative stress. In humans, inherited DNA sequence polymorphisms that decrease Nrf2 abundance have been linked to various diseases of the skin, lung, stomach, and intestine, which are all organs that are subjected to environmental stressors. Thus, individuals genetically predisposed to a suboptimal antioxidant response may be more susceptible to disorders caused or exacerbated by oxidative stress. Like many diseases, the aging process is also linked to oxidative stress, and studies in model organisms show that Cnc transcription factors promote longevity. Paradoxically, in aging and in advanced human respiratory and neurodegenerative disease, the Cnc antioxidant response is suppressed. Thus, Nrf2-activating compounds could be beneficial in the treatment of human diseases and might help extend the healthy life span. However, hyperactivation of the antioxidant response is detrimental in model organisms and has been linked to chemoresistant cancers in humans. These observations caution that sustained induction of Cnc factors can be deleterious and indicate that the antioxidant response system must be tightly controlled; moreover, they imply that compounds inhibiting Nrf2 may also be useful therapeutics as chemotherapy sensitizers. This Review, with 3 figures, 2 tables, and 321 citations, describes the stress-activated Cnc transcription factors, their regulatory mechanisms, and their roles in aging and human disease.

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

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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 »
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.
   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
   Abstract »    Full Text »    PDF »
Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency.
N. Y. Marcus, K. Blomenkamp, M. Ahmad, and J. H. Teckman (2012)
Exp Biol Med 237, 1163-1172
   Abstract »    Full Text »    PDF »
Identification of UV-protective Activators of Nuclear Factor Erythroid-derived 2-Related Factor 2 (Nrf2) by Combining a Chemical Library Screen with Computer-based Virtual Screening.
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 »
Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathway in mice.
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
   Abstract »    Full Text »    PDF »
NF-E2-Related Factor 1 (Nrf1) Serves as a Novel Regulator of Hepatic Lipid Metabolism through Regulation of the Lipin1 and PGC-1{beta} Genes.
Y. Hirotsu, N. Hataya, F. Katsuoka, and M. Yamamoto (2012)
Mol. Cell. Biol. 32, 2760-2770
   Abstract »    Full Text »    PDF »
{alpha}-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease.
I. Lastres-Becker, A. Ulusoy, N. G. Innamorato, G. Sahin, A. Rabano, D. Kirik, and A. Cuadrado (2012)
Hum. Mol. Genet. 21, 3173-3192
   Abstract »    Full Text »    PDF »
Dual Regulation of the Transcriptional Activity of Nrf1 by {beta}-TrCP- and Hrd1-Dependent Degradation Mechanisms.
Y. Tsuchiya, T. Morita, M. Kim, S.-i. Iemura, T. Natsume, M. Yamamoto, and A. Kobayashi (2011)
Mol. Cell. Biol. 31, 4500-4512
   Abstract »    Full Text »    PDF »
Nrf2 Represses FGF21 During Long-Term High-Fat Diet-Induced Obesity in Mice.
D. V. Chartoumpekis, P. G. Ziros, A. I. Psyrogiannis, A. G. Papavassiliou, V. E. Kyriazopoulou, G. P. Sykiotis, and I. G. Habeos (2011)
Diabetes 60, 2465-2473
   Abstract »    Full Text »    PDF »
Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease.
M. C. Barone, G. P. Sykiotis, and D. Bohmann (2011)
Dis. Model. Mech. 4, 701-707
   Abstract »    Full Text »    PDF »
Transcriptional regulation of xenobiotic detoxification in Drosophila.
J. R. Misra, M. A. Horner, G. Lam, and C. S. Thummel (2011)
Genes & Dev. 25, 1796-1806
   Abstract »    Full Text »    PDF »
Genetic Deletion of Nrf2 Promotes Immortalization and Decreases Life Span of Murine Embryonic Fibroblasts.
L. Jodar, E. M. Mercken, J. Ariza, C. Younts, J. A. Gonzalez-Reyes, F. J. Alcain, I. Buron, R. de Cabo, and J. M. Villalba (2011)
J Gerontol A Biol Sci Med Sci 66A, 247-256
   Abstract »    Full Text »    PDF »
Basic Leucine Zipper Protein Cnc-C Is a Substrate and Transcriptional Regulator of the Drosophila 26S Proteasome.
K. B. Grimberg, A. Beskow, D. Lundin, M. M. Davis, and P. Young (2011)
Mol. Cell. Biol. 31, 897-909
   Abstract »    Full Text »    PDF »
SKN-1/Nrf2 Inhibits Dopamine Neuron Degeneration in a Caenorhabditis elegans Model of Methylmercury Toxicity.
N. VanDuyn, R. Settivari, G. Wong, and R. Nass (2010)
Toxicol. Sci. 118, 613-624
   Abstract »    Full Text »    PDF »
Genetic Mechanisms of Coffee Extract Protection in a Caenorhabditis elegans Model of {beta}-Amyloid Peptide Toxicity.
V. Dostal, C. M. Roberts, and C. D. Link (2010)
Genetics 186, 857-866
   Abstract »    Full Text »    PDF »
Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1.
K. Taguchi, J. M. Maher, T. Suzuki, Y. Kawatani, H. Motohashi, and M. Yamamoto (2010)
Mol. Cell. Biol. 30, 3016-3026
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882