title: Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis.
abstract: Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2), a transcription factor that regulates inducible expression of detoxifying enzymes, is critical in preventing N-nitrosobutyl(4-hydroxybutyl)amine (BBN)-induced urinary bladder carcinogenesis. To explore whether Nrf2 and the tumor suppressor p53 cooperatively act in tumor prevention, we investigated the susceptibility of Nrf2-/-::p53+/- mice to BBN-induced urinary bladder carcinogenesis. The incidence of BBN-induced urinary bladder carcinoma was 63.0% in Nrf2-/- mice (P = 0.115), 75.8% in p53+/- mice (P < 0.01) and 89.6% in Nrf2-/-::p53+/- mice (P < 0.01) compared with 37.9% in wild-type. Higher incidence of carcinoma was observed in Nrf2-/-::p53+/- mice when compared with either Nrf2-/- (P < 0.01) or p53+/- mice (P = 0.382). Similarly, muscular invasive carcinoma incidence was higher in Nrf2-/-::p53+/- mice (62.0%) than either wild-type (6.9%, P < 0.01), p53+/- (38.0%, P = 0.110) or Nrf2-/- mice (3.7%, P < 0.01). Furthermore, urinary concentrations of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN, were only increased when Nrf2 but not p53 was disrupted. These results demonstrate that tumor susceptibility is synergistically exacerbated in Nrf2-/-::p53+/- mice due to poor detoxification and accelerated proliferation in comparison with either single mutant alone. BBN administration increased p53-mediated expression of p21, Mdm2 and Bax, and the inducible expression of p21 was significantly enhanced in Nrf2-/- mice. Conversely, modest increases in NAD(P)H dehydrogenase, quinone 1 (NQO1) and uridine diphosphate (UDP) glucuronosyltransferase 1A6 (UGT1A6) expression were observed in p53+/- compared with those of wild-type mice after BBN exposure. These results thus reveal potential interactions between p53 and Nrf2 and their gene batteries, and indicate that both factors cooperatively contribute to tumor prevention.
authors.affiliation: Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Iida
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Maher
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Oyasu
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mori
authors.forename: Toru
authors.initials: T
authors.lastname: Shimazui
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Akaza
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001483:Base Sequence; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
chemical_list: D002273:Carcinogens; D017931:DNA Primers; D051267:NF-E2-Related Factor 2; D016159:Tumor Suppressor Protein p53; D002085:Butylhydroxybutylnitrosamine