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

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2010 Mar 11

PMID 20215646

Citations 422

Authors

Gerasimos P Sykiotis

Dirk Bohmann

Affiliations

Soon will be listed here.

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.

Citing Articles

Fatty acid synthase inhibition improves hypertension-induced erectile dysfunction by suppressing oxidative stress and NLRP3 inflammasome-dependent pyroptosis through activating the Nrf2/HO-1 pathway.

Luan J, Yu M, Gu Q, Zhou X, Shao Y, Chen T Front Immunol. 2025; 15:1532021.

PMID: 39877365 PMC: 11772187. DOI: 10.3389/fimmu.2024.1532021.

Role of NRF2 in Pathogenesis of Alzheimer's Disease.

Chu C, Uruno A, Katsuoka F, Yamamoto M Antioxidants (Basel). 2025; 13(12.

PMID: 39765857 PMC: 11727090. DOI: 10.3390/antiox13121529.

Transcription factor NF-E2-related factor 2 plays a critical role in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) by regulating ferroptosis.

Deng J, Li N, Hao L, Li S, Aiyu N, Zhang J PeerJ. 2024; 12:e17692.

PMID: 39670103 PMC: 11637007. DOI: 10.7717/peerj.17692.

Systematic regulation of immune checkpoint molecules by redox regulators CNC-bZIP transcription factors.

Ning H, Yang Q, Ren Y, Qiu L Discov Oncol. 2024; 15(1):685.

PMID: 39565431 PMC: 11579261. DOI: 10.1007/s12672-024-01574-0.

Genetic Variations in the Microsatellite Contribute to the Regulation of Bovine Sperm-Borne Antioxidant Capacity.

Anwar K, Thaller G, Saeed-Zidane M Cells. 2024; 13(19.

PMID: 39404365 PMC: 11482559. DOI: 10.3390/cells13191601.

References

Motohashi H, OConnor T, Katsuoka F, Engel J, Yamamoto M . Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene. 2002; 294(1-2):1-12. DOI: 10.1016/s0378-1119(02)00788-6. View

Zipper L, Mulcahy R . The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem. 2002; 277(39):36544-52. DOI: 10.1074/jbc.M206530200. View

Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H . Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 2002; 21(19):5216-24. PMC: 129038. DOI: 10.1093/emboj/cdf516. View

Tarumoto T, Nagai T, Ohmine K, Miyoshi T, Nakamura M, Kondo T . Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol. 2004; 32(4):375-81. DOI: 10.1016/j.exphem.2004.01.007. View

Derjuga A, Gourley T, Holm T, Heng H, Shivdasani R, Ahmed R . Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus. Mol Cell Biol. 2004; 24(8):3286-94. PMC: 381672. DOI: 10.1128/MCB.24.8.3286-3294.2004. View

Tashiro S, Muto A, Tanimoto K, Tsuchiya H, Suzuki H, Hoshino H . Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2. Mol Cell Biol. 2004; 24(8):3473-84. PMC: 381671. DOI: 10.1128/MCB.24.8.3473-3484.2004. View

Cullinan S, Diehl J . PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem. 2004; 279(19):20108-17. DOI: 10.1074/jbc.M314219200. View

Motohashi H, Katsuoka F, Engel J, Yamamoto M . Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Proc Natl Acad Sci U S A. 2004; 101(17):6379-84. PMC: 404053. DOI: 10.1073/pnas.0305902101. View

Shen G, Hebbar V, Nair S, Xu C, Li W, Lin W . Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein. J Biol Chem. 2004; 279(22):23052-60. DOI: 10.1074/jbc.M401368200. View

10.

Bacskai B, Hyman B . Alzheimer's disease: what multiphoton microscopy teaches us. Neuroscientist. 2002; 8(5):386-90. DOI: 10.1177/107385802236963. View

11.

Huang H, Nguyen T, Pickett C . Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem. 2002; 277(45):42769-74. DOI: 10.1074/jbc.M206911200. View

12.

Braak H, Del Tredici K, Rub U, de Vos R, Jansen Steur E, Braak E . Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2002; 24(2):197-211. DOI: 10.1016/s0197-4580(02)00065-9. View

13.

Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even P . IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2002; 421(6919):182-7. DOI: 10.1038/nature01298. View

14.

Bonifati V, Rizzu P, van Baren M, Schaap O, Breedveld G, Krieger E . Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2002; 299(5604):256-9. DOI: 10.1126/science.1077209. View

15.

Ramos-Gomez M, Dolan P, Itoh K, Yamamoto M, Kensler T . Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis. 2003; 24(3):461-7. DOI: 10.1093/carcin/24.3.461. View

16.

Lee J, Calkins M, Chan K, Kan Y, Johnson J . Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem. 2003; 278(14):12029-38. DOI: 10.1074/jbc.M211558200. View

17.

Shih A, Johnson D, Wong G, Kraft A, Jiang L, Erb H . Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci. 2003; 23(8):3394-406. PMC: 6742304. View

18.

Aono J, Yanagawa T, Itoh K, Li B, Yoshida H, Kumagai Y . Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts. Biochem Biophys Res Commun. 2003; 305(2):271-7. DOI: 10.1016/s0006-291x(03)00728-9. View

19.

Chen L, Kwong M, Lu R, Ginzinger D, Lee C, Leung L . Nrf1 is critical for redox balance and survival of liver cells during development. Mol Cell Biol. 2003; 23(13):4673-86. PMC: 164851. DOI: 10.1128/MCB.23.13.4673-4686.2003. View

20.

Numazawa S, Ishikawa M, Yoshida A, Tanaka S, Yoshida T . Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress. Am J Physiol Cell Physiol. 2003; 285(2):C334-42. DOI: 10.1152/ajpcell.00043.2003. View