Stress-Activated Cap’n’collar Transcription Factors in Aging and Human Disease
By Gerasimos P. Sykiotis, D. Bohmann. Science Signaling, 2010
775 citations recorded by the source corpus.
The oxidative stress response is an attractive target for treating human diseases and extending the healthy life span. 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. 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.
Subfields: Cell Biology, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/2d521e0ba53207cd198661475e77259f630c64ad
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Citations in the corpus
- Oxidative stress response and Nrf2 signaling in aging. (2015, neutral): “The tightly regulated nucleophilic tone becomes compromised with aging, and leads to a chronic oxidative state in old organisms [10, 11].”
- TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO (2012, background): “DAF-16 and SKN-1 regulate genes that protect against environmental, metabolic, and proteotoxic stress, and promote longevity in various species (Kenyon, 2010; Kwon et al., 2010; Li et al., 2011; Oliveira et al., 2009; Sykiotis and Bohmann, 2010; Tullet et al., 2008).”
- Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer (2018, background): “Subsequently, the stabilized NRF2 translocates into the nucleus, binds to antioxidant response elements (AREs) in gene promoter regions, and regulates the transcription of a host of target genes involved in the antioxidant response and cellular redox maintenance, including GCL and GR discussed in th”
- How Do Nutritional Antioxidants Really Work: Nucleophilic Tone and Para-Hormesis Versus Free Radical Scavenging in vivo (2013, neutral): “Activation of the Nrf2 transcription factor and the electrophile response element, EpRE (also called the antioxidant response element or ARE) to which Nrf2 binds [69–79] are key in adaptive responses to various oxidative stimuli [80, 81].”
- Small Molecule Modulators of Keap1-Nrf2-ARE Pathway as Potential Preventive and Therapeutic Agents (2012, background): “Mechanistically, thiol-selenide or selenol-sulfide exchange is well known due to the similar electronegativity of sulfur and selenium.239 Selenites and various organoselenium compounds are reported to have cytoprotective activities.240 Interestingly, SFN-isoSe (80), a selenium isostere of SFN (60) w”
- Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022, background): “Progressive and irreversible oxidative damage accumulates with age and diminishes critical aspects of cell physiology [57,201,202].”
- Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism (2016, background): “NF-E2 p45-related factors 1 and 3 (Nrf1 and Nrf3) as well as transcriptional repressors Bach1 and Bach2 are the members of the family (reviewed in [4]).”