Carcinogenesis Advance Access published online on June 29, 2007
Carcinogenesis, doi:10.1093/carcin/bgm146
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Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis
1 Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, Japan
2 Center for TARA, Institute of Basic Medical Sciences, and JST-ERATO Environmental Response Project, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, Japan
3 Institute of Community Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, Japan
4 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
5 Institute of Biological of Pharmacy, Gifu Pharmaceutical University, Mitahora-higashi 5-6-1, Gifu, Japan
6 Corresponding author, Please send correspondence to Masayuki Yamamoto at Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan, TEL 81-298-53-6158; FAX 81-298-53-7318, E-mail: masi{at}tara.tsukuba.ac.jp, E-mail address for Ken Itoh: itohk{at}cc.hirosaki-u.ac.jp
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 to 37.9% in wild-type. Higher incidence of carcinoma was observed in Nrf2–/–::p53+/– mice when compared to 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 BCPN, 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 of NQO1 and UGT1A6 expression were observed in p53+/– compared to 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.
Key Words: detoxifying enzymes • urinary bladder carcinogenesis • Nrf2 • p53
Received February 1, 2007; revised May 24, 2007; accepted June 18, 2007.
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