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Sci. Signal., 9 March 2010
Vol. 3, Issue 112, p. re3
Stress-Activated Cap'n'collar Transcription Factors in Aging and Human Disease
Gerasimos P. Sykiotis1,2* and
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: Capncollar (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.
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
|Abstract »|Full Text »|PDF »
Basic Leucine Zipper Protein Cnc-C Is a Substrate and Transcriptional Regulator of the Drosophila 26S Proteasome.