Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma

Abstract

We have previously generated mice deficient for Nfe213 (NF-E2 p45 related factor 3 or Nrf3), a member of the cap 'n' collar family of basic-leucine zipper transcription factors. To examine whether Nrf3 is involved in chemical-induced carcinogenesis, we exposed the mice to benzo- IntroductionThe polycyclic hydrocarbon benzo[a]pyrene (B[a]P) is an environmental pollutant, a major component of cigarette smoke, and a well-characterized rodent and human carcinogen. 1 For instance, B[a]P can induce lymphoma in different genetically modified mouse models. 2,3 Biotransformation of B[a]P is a requisite for its detoxification and excretion. The first step is catalyzed by cytochrome P450-dependent mono-oxygenases (phase I), and their products are subsequently coupled to endogenous metabolites (phase II). 4 However, certain reactive intermediates interact covalently with DNA to form adducts that ultimately result in mutagenicity and/or carcinogenicity. It has been reported that absence of the cap 'n' collar (CNC) factor Nrf2 renders mice more susceptible to tumorigenesis caused by B[a]P 5,6 probably because of an incapacity to detoxify the carcinogen. These data provided a link between CNC factormediated induction of phase II and antioxidant enzymes and the susceptibility to carcinogens.The CNC family includes p45 NFE2, NRF1, NRF2, NRF3, BACH1, and BACH2 proteins and can form heterodimers with small MAF proteins. We and others previously identified NRF3 as an endoplasmic reticulum-associated protein that is Asn-glycosylated. 7,8 We showed that Nrf3 gene expression is induced by butylated hydroxytoluene in the lung of mice. 9 Recently, Pepe et al showed a role for Nrf3 in smooth muscle cell differentiation. 10 We have generated mice lacking a functional Nrf3 and found that these mice do not show any obvious abnormalities under nonchallenging conditions. 11 Thus, to investigate whether the mice deficient for Nrf3 are tumor-prone, we challenged the mice with the carcinogen B[a]P. Our studies revealed a novel role for Nrf3 in the protection of mice against carcinogen-induced lymphomagenesis.

NFE2L3 (NRF3): the Cinderella of the Cap‘n’Collar transcription factors

“…Absence of NFE2L3 renders the mice susceptible to carcinogen-induced lymphomagenesis [98], suggesting a possible role for NFE2L3 in the regulation of T cells. The fact that NFE2L3 transcripts have been found to be elevated in many different cancer types in gene expression profiling studies [83][84][85][100][101][102][103][104][105] suggests a link of NFE2L3 to human cancer.…”

“…Linking NFE2L3 and carcinogenesis: in vivo evidence from mouse model Recent in vivo data linked the NFE2L3 transcription factor to protection against lymphomagenesis [98]. Nfe2l3 -/-mice exposed for four consecutive weeks to benzo[a]pyrene (B[a]P), a carcinogen present in tobacco smoke [99], exhibited significantly increased mortality compared to wild-type animals.…”

Role of Nrf2 in Oxidative Stress and Toxicity

“…The CNC bZip proteins possess considerable similarities in their structure, DNA recognition sequence, and target genes, reflecting an evolutionary link to erythropoiesis essential for oxygen utilization in vertebrates. Among the proteins, NFE2 is critical for erythrocyte and platelet development (6); Bach1 and Bach2 act as suppressors of transcription by NFE2 (75); Nrf1 is required for embryonic hepatic hematopoiesis but has also evolved to aid in resistance to ER stress, oxidant stress, and metal toxicity (76); Nrf2 deviates from most CNC bZip proteins to become specialized in oxidant resistance; Nrf3 is less well understood but may contribute to smooth muscle cell differentiation from stem cells toward vascular lineage and to in vivo protection against hematopoietic malignancy (77)(78)(79). In invertebrates, Caenorhabditis elegans protein skinhead-1 (SKN-1) has significant homology with Nrf2 and binds to an ARE-like element to regulate oxidative stress-related genes (80).…”

“…Six of the seven lysine residues of the helix face one side. A conserved ETGE sequence (a.a. [79][80][81][82] locates in the hydrophobic hairpin loop between the two β-sheets. A second conserved sequence DLG (a.a. [29][30][31] follows another β-hairpin structure (a.a. [25][26][27][28][29].…”

New developments in the pathology of malignant lymphoma: a review of the literature published from November 2010–January 2011

“…Another mouse model for T-ALL is reported by Chevillard et al [13]. They exposed mice deficient for Nrf3 (NF-E2-related factor) to benzoapyrene, a carcinogen found in cigarette smoke.…”