Complexity of CNC Transcription Factors As Revealed by Gene Targeting of the Nrf3 Locus

Abstract

Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3 ؊/؊ mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3 ؊/؊ mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3 ؊/؊ /Nrf2 ؊/؊ and Nrf3 ؊/؊ /p45 ؊/؊ mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.

Nuclear Factor-E2-related Factor-1 Mediates Ascorbic Acid Induction of Osterix Expression via Interaction with Antioxidant-Responsive Element in Bone Cells

“…Blockage of 80% Nrf1 expression by RNA interference diminished Nrf1 competition of ARE sites with other repressors (26), therefore abolishing AA induction of osterix expression and significantly impairing BMS cell differentiation and nodule information in vitro. Interestingly, it has been reported that disruption of Nrf1, but not Nrf2 or Nrf3, leads to embryonic lethality and causes anemia, a phenotype that is also seen in the sfx mutant mice, due to down-regulation of ␤-globin (35)(36)(37). In addition, although both Nrf1 and Nrf2 are expressed in the liver, only the liver-specific conditional knock-out of Nrf1 showed oxidative stress and impaired expression of various ARE-containing antioxidant genes, and developed liver cancer (38 -40).…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…The CNC domain, comprising a sequence of 43 conserved amino acids, is located N-terminally to the basic DNA-binding domain. The family members of the CNC domain heterodimerise with small Maf proteins (Derjuga et al 2004) and exhibit high homology in their DNA binding and leucine zipper domains; however, their biological functions are different. Most of the CNC family members are transcription activators, but Bach1 and Bach2 are transcription repressors.…”

Nrf2 Transcriptionally Activates the mafG Gene through an Antioxidant Response Element

“…The ARE-dependent HO-1 gene was significantly derepressed in bach1-null mutant mice, suggesting that HO-1 is negatively regulated by Bach1 (9). Although nrf3-null and bach2-null mutant mice have been reported (10,11), the contribution of these factors to AREmediated regulation is still to be determined.…”