title: Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels.
abstract: Transcription factor Nrf2 (NF-E2-related factor 2) is essential for oxidative and electrophilic stress responses. While it has been well characterized that Nrf2 activity is tightly regulated at the protein level through proteasomal degradation via Keap1 (Kelch-like ECH-associated protein 1)-mediated ubiquitination, not much attention has been paid to the supply side of Nrf2, especially regulation of Nrf2 gene transcription. Here we report that manipulation of Nrf2 transcription is effective in changing the final Nrf2 protein level and activity of cellular defense against oxidative stress even in the presence of Keap1 and under efficient Nrf2 degradation, determined using genetically engineered mouse models. In excellent agreement with this finding, we found that minor A/A homozygotes of a single nucleotide polymorphism (SNP) in the human NRF2 upstream promoter region (rs6721961) exhibited significantly diminished NRF2 gene expression and, consequently, an increased risk of lung cancer, especially those who had ever smoked. Our results support the notion that in addition to control over proteasomal degradation and derepression from degradation/repression, the transcriptional level of the Nrf2 gene acts as another important regulatory point to define cellular Nrf2 levels. These results thus verify the critical importance of human SNPs that influence the levels of transcription of the NRF2 gene for future personalized medicine.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Kai
authors.initials: K
authors.lastname: Takaya
authors.forename: Kouya
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Hideo
authors.initials: H
authors.lastname: Kunitoh
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.forename: Koh
authors.initials: K
authors.lastname: Furuta
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000096:biosynthesis; D012306:Risk; D012907:Smoking; D014158:Transcription, Genetic; D054875:Ubiquitination; D018631:ras Proteins / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117307:KRAS protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins