{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T08:00:56Z","timestamp":1779350456352,"version":"3.51.4"},"reference-count":54,"publisher":"Portland Press Ltd.","issue":"4","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,8,1]]},"abstract":"<jats:p>The nuclear erythroid 2-like 2 transcription factor (NRF2), is a major regulator of cellular redox balance. Although NRF2 activation is generally regarded as beneficial to human health, recent studies have identified that sustained NRF2 activation is over-represented in many cancers. This raises the question regarding the role of NRF2 activation in the development and progression of those cancers. This review focuses on the mechanisms and the effects of NRF2 activation in two hereditary cancer predisposition syndromes: hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary tyrosinemia type\u00a01 (HT1). Because the cancer initiating mutations in these hereditary syndromes are well defined, they offer a unique opportunity to explore the roles of NRF2 activation in the early stages of carcinogenesis. Over the years, a variety of approaches have been utilized to study the biology of HLRCC and HT1. In HLRCC, in\u00a0vitro studies have demonstrated the importance of NRF2 activation in sustaining cancer cell proliferation. In the mouse model of HT1 however, NRF2 activation seems to protect cells from malignant transformation. In both HT1 and HLRCC, NRF2 activation promotes the clearance of electrophilic metabolites, enabling cells to survive cancer-initiating mutations. Biological insights gained from the hereditary syndromes\u2019 studies may shed light on to the roles of NRF2 activation in sporadic tumours.<\/jats:p>","DOI":"10.1042\/bst20150041","type":"journal-article","created":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T16:51:05Z","timestamp":1439311865000},"page":"650-656","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Sustained NRF2 activation in hereditary leiomyomatosis and renal cell cancer (HLRCC) and in hereditary tyrosinemia type\u00a01 (HT1)"],"prefix":"10.1042","volume":"43","author":[{"given":"Ivraj Singh","family":"Sandhu","sequence":"first","affiliation":[{"name":"Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas\u00a0James","family":"Maksim","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva\u00a0Alice","family":"Amouzougan","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryce\u00a0Wilson","family":"Gallion","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony\u00a0L.J.","family":"Raviele","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aikseng","family":"Ooi","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona 85721, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2015,8,3]]},"reference":[{"key":"2021111820083412800_B1","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1089\/ars.2014.5914","article-title":"Focusing at the double-edged sword of redox imbalance: signals for cell survival or for cell death?","volume":"21","author":"Pietraforte","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"2021111820083412800_B2","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1080\/10715769900300881","article-title":"Regulatory mechanisms of cellular response to oxidative stress","volume":"31","author":"Itoh","year":"1999","journal-title":"Free Radic. Res."},{"key":"2021111820083412800_B3","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.ccr.2012.05.016","article-title":"Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming","volume":"22","author":"Mitsuishi","year":"2012","journal-title":"Cancer Cell"},{"key":"2021111820083412800_B4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1042\/bst0280033","article-title":"The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin","volume":"28","author":"Hayes","year":"2000","journal-title":"Biochem. Soc. Trans."},{"key":"2021111820083412800_B5","doi-asserted-by":"publisher","first-page":"18399","DOI":"10.1074\/jbc.M100103200","article-title":"Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors","volume":"276","author":"Kim","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021111820083412800_B6","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cbi.2010.09.025","article-title":"The cap\u2019n\u2019collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics","volume":"192","author":"Higgins","year":"2011","journal-title":"Chem.-Biol. Interact."},{"key":"2021111820083412800_B7","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1101\/gad.238246.114","article-title":"Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis","volume":"28","author":"Wu","year":"2014","journal-title":"Genes Dev."},{"key":"2021111820083412800_B8","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1128\/MCB.01204-10","article-title":"SCF\/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner","volume":"31","author":"Rada","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"2021111820083412800_B9","doi-asserted-by":"publisher","first-page":"3765","DOI":"10.1038\/onc.2012.388","article-title":"Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity","volume":"32","author":"Chowdhry","year":"2013","journal-title":"Oncogene"},{"key":"2021111820083412800_B10","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.tibs.2014.02.002","article-title":"The Nrf2 regulatory network provides an interface between redox and intermediary metabolism","volume":"39","author":"Hayes","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"2021111820083412800_B11","doi-asserted-by":"publisher","first-page":"10941","DOI":"10.1128\/MCB.24.24.10941-10953.2004","article-title":"Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex","volume":"24","author":"Zhang","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2021111820083412800_B12","doi-asserted-by":"publisher","first-page":"7130","DOI":"10.1128\/MCB.24.16.7130-7139.2004","article-title":"Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2","volume":"24","author":"Kobayashi","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2021111820083412800_B13","doi-asserted-by":"publisher","first-page":"11908","DOI":"10.1073\/pnas.172398899","article-title":"Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants","volume":"99","author":"Dinkova-Kostova","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111820083412800_B14","doi-asserted-by":"publisher","first-page":"8137","DOI":"10.1128\/MCB.23.22.8137-8151.2003","article-title":"Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress","volume":"23","author":"Zhang","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2021111820083412800_B15","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1089\/ars.2010.3221","article-title":"Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway","volume":"13","author":"Hayes","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"2021111820083412800_B16","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.toxlet.2014.05.018","article-title":"Targeting Nrf2-Keap1 signaling for chemoprevention of skin carcinogenesis with bioactive phytochemicals","volume":"229","author":"Chun","year":"2014","journal-title":"Toxicol. Lett."},{"key":"2021111820083412800_B17","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.pneurobio.2012.09.003","article-title":"Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection","volume":"100","author":"Zhang","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"2021111820083412800_B18","first-page":"S128","article-title":"Direct and indirect antioxidant properties of inducers of cytoprotective proteins","volume":"52","author":"Dinkova-Kostova","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"2021111820083412800_B19","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1053\/j.jrn.2011.10.012","article-title":"Dietary and synthetic activators of the antistress gene response in treatment of renal disease","volume":"22","author":"Thornalley","year":"2012","journal-title":"J. Renal Nutr."},{"key":"2021111820083412800_B20","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1073\/pnas.0505723102","article-title":"Activation of the Keap1\/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers","volume":"103","author":"Satoh","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111820083412800_B21","doi-asserted-by":"publisher","first-page":"850","DOI":"10.2337\/db09-1342","article-title":"The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy","volume":"59","author":"Jiang","year":"2010","journal-title":"Diabetes"},{"key":"2021111820083412800_B22","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1172\/JCI200421146","article-title":"Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice","volume":"114","author":"Rangasamy","year":"2004","journal-title":"J. Clin. Invest."},{"key":"2021111820083412800_B23","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1073\/pnas.0804333106","article-title":"Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice","volume":"106","author":"Sussan","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111820083412800_B24","doi-asserted-by":"publisher","first-page":"2325","DOI":"10.1073\/pnas.0712162105","article-title":"Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction","volume":"105","author":"Pearson","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111820083412800_B25","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1185\/03007995.2013.849236","article-title":"BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety","volume":"30","author":"Fox","year":"2014","journal-title":"Curr. Med. Res. Opin."},{"key":"2021111820083412800_B26","doi-asserted-by":"publisher","first-page":"2179","DOI":"10.1101\/gad.225680.113","article-title":"The emerging role of the Nrf2-Keap1 signaling pathway in cancer","volume":"27","author":"Jaramillo","year":"2013","journal-title":"Genes Dev."},{"key":"2021111820083412800_B27","doi-asserted-by":"publisher","first-page":"e420","DOI":"10.1371\/journal.pmed.0030420","article-title":"Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer","volume":"3","author":"Singh","year":"2006","journal-title":"PLoS Med."},{"key":"2021111820083412800_B28","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1002\/path.2653","article-title":"Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin","volume":"220","author":"Kim","year":"2010","journal-title":"J. Pathol."},{"key":"2021111820083412800_B29","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1158\/0008-5472.CAN-12-3227","article-title":"CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma","volume":"73","author":"Ooi","year":"2013","journal-title":"Cancer Res."},{"key":"2021111820083412800_B30","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.ccr.2011.08.024","article-title":"An antioxidant response phenotype shared between hereditary and sporadic type\u00a02 papillary renal cell carcinoma","volume":"20","author":"Ooi","year":"2011","journal-title":"Cancer Cell"},{"key":"2021111820083412800_B31","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/jid.2013.343","article-title":"A somatic mutation of the KEAP1 gene in malignant melanoma is involved in aberrant NRF2 activation and an increase in intrinsic drug resistance","volume":"134","author":"Miura","year":"2014","journal-title":"J. Invest. Dermatol."},{"key":"2021111820083412800_B32","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nature12912","article-title":"Discovery and saturation analysis of cancer genes across 21 tumour types","volume":"505","author":"Lawrence","year":"2014","journal-title":"Nature"},{"key":"2021111820083412800_B33","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1158\/1535-7163.MCT-09-0589","article-title":"Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth","volume":"9","author":"Zhang","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"2021111820083412800_B34","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1089\/ars.2010.3219","article-title":"Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance","volume":"13","author":"Singh","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"2021111820083412800_B35","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.ccr.2011.09.006","article-title":"Renal cyst formation in Fh1-deficient mice is independent of the Hif\/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling","volume":"20","author":"Adam","year":"2011","journal-title":"Cancer Cell"},{"key":"2021111820083412800_B36","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1002\/hep.22391","article-title":"Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type\u00a01 and its role in survival and tumor development","volume":"48","author":"Marhenke","year":"2008","journal-title":"Hepatology"},{"key":"2021111820083412800_B37","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/ng849","article-title":"Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer","volume":"30","author":"Tomlinson","year":"2002","journal-title":"Nat. Genet."},{"key":"2021111820083412800_B38","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1136\/jmg.2010.085068","article-title":"Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type\u00a02 papillary renal cell carcinoma","volume":"48","author":"Gardie","year":"2011","journal-title":"J. Med. Genet."},{"key":"2021111820083412800_B39","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1111\/j.1399-0004.2010.01486.x","article-title":"Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis","volume":"79","author":"Smit","year":"2011","journal-title":"Clin. Genet."},{"key":"2021111820083412800_B40","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s10689-011-9428-z","article-title":"Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics","volume":"10","author":"Lehtonen","year":"2011","journal-title":"Familial Cancer"},{"key":"2021111820083412800_B41","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/s10689-014-9703-x","article-title":"Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC)","volume":"13","author":"Wong","year":"2014","journal-title":"Familial Cancer"},{"key":"2021111820083412800_B42","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.ccr.2007.02.005","article-title":"Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway","volume":"11","author":"Pollard","year":"2007","journal-title":"Cancer Cell"},{"key":"2021111820083412800_B43","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1093\/hmg\/ddi227","article-title":"Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations","volume":"14","author":"Pollard","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"2021111820083412800_B44","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.molcel.2013.05.003","article-title":"The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling","volume":"51","author":"Sullivan","year":"2013","journal-title":"Mol. Cell"},{"key":"2021111820083412800_B45","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.ccell.2014.10.005","article-title":"Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer","volume":"26","author":"Sourbier","year":"2014","journal-title":"Cancer Cell"},{"key":"2021111820083412800_B46","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/ajmg.c.30092","article-title":"The genetic tyrosinemias","volume":"142C","author":"Scott","year":"2006","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2021111820083412800_B47","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1007\/s00109-005-0648-2","article-title":"Tyrosinaemia type\u00a0I\u2013de novo mutation in liver tissue suppressing an inborn splicing defect","volume":"83","author":"Bliksrud","year":"2005","journal-title":"J. Mol. Med."},{"key":"2021111820083412800_B48","doi-asserted-by":"publisher","first-page":"4641","DOI":"10.1073\/pnas.74.10.4641","article-title":"On the enzymic defects in hereditary tyrosinemia","volume":"74","author":"Lindblad","year":"1977","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111820083412800_B49","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1101\/gad.6.8.1430","article-title":"Deficiency of an enzyme of tyrosine metabolism underlies altered gene expression in newborn liver of lethal albino mice","volume":"6","author":"Ruppert","year":"1992","journal-title":"Genes Dev."},{"key":"2021111820083412800_B50","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/0378-1119(91)90250-F","article-title":"Cloning and expression analysis of a cDNA encoding fumarylacetoacetate hydrolase: post-transcriptional modulation in rat liver and kidney","volume":"104","author":"Labelle","year":"1991","journal-title":"Gene"},{"key":"2021111820083412800_B51","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/0140-6736(92)92685-9","article-title":"Treatment of hereditary tyrosinaemia type\u00a0I by inhibition of 4-hydroxyphenylpyruvate dioxygenase","volume":"340","author":"Lindstedt","year":"1992","journal-title":"Lancet"},{"key":"2021111820083412800_B52","doi-asserted-by":"publisher","first-page":"2298","DOI":"10.1101\/gad.7.12a.2298","article-title":"Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice","volume":"7","author":"Grompe","year":"1993","journal-title":"Genes Dev."},{"key":"2021111820083412800_B53","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0891-5849(03)00273-9","article-title":"Pharmacological rescue of the 14CoS\/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress","volume":"35","author":"Dieter","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"2021111820083412800_B54","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1006\/bbrc.1997.6220","article-title":"The mutagenicity of the tyrosine metabolite, fumarylacetoacetate, is enhanced by glutathione depletion","volume":"232","author":"Jorquera","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["Biochemical Society Transactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/43\/4\/650\/431105\/bst0430650.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/43\/4\/650\/431105\/bst0430650.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T20:18:39Z","timestamp":1637266719000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article\/43\/4\/650\/88448\/Sustained-NRF2-activation-in-hereditary"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,1]]},"references-count":54,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,8,3]]},"published-print":{"date-parts":[[2015,8,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bst20150041","relation":{},"ISSN":["0300-5127","1470-8752"],"issn-type":[{"value":"0300-5127","type":"print"},{"value":"1470-8752","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,1]]}}}