Transcription factor Nrf2 maintains the basal expression of Mdm2: An implication of the regulation of p53 signaling by Nrf2

• Published in: Archives of biochemistry and biophysics 2011-03, Vol.507 (2), p.356-364
• Main Authors: You, Aram, Nam, Chang-won, Wakabayashi, Nobunao, Yamamoto, Masayuki, Kensler, Thomas W., Kwak, Mi-Kyoung
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Antioxidants - metabolism; Apoptosis; Cell death; Cell fate; Cell Line, Tumor; DNA microarrays; Embryo fibroblasts; Environmental stress; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation; HEK293 Cells; Humans; Hydrogen peroxide; Introns; Introns - genetics; Mdm2; MDM2 protein; MEFs; Mice; NF-E2-Related Factor 2 - deficiency; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Ovarian carcinoma; Oxidative stress; p53; p53 protein; Polymerase chain reaction; Promoter Regions, Genetic - genetics; Promoters; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Regulatory sequences; Response Elements - genetics; Signal Transduction; Transcription factors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2010.12.034

► We demonstrate that the expression of Mdm2 is diminished in nrf2-deleted MEFs. ► Nrf2 directly involves in the regulation of the basal expression of Mdm2 through the antioxidant response element. ► p53 protein was accumulated in nrf2-deleted MEFs. ► In human ovarian cancer cells, Nrf2 inhibition by shRNA increased p53 signaling to enhance cell death in response to hydrogen peroxide treatment. Co-operated regulation of oxidative stress–response transcription factors would be an important issue for animals to determine the cell fate under environmental stress. This notion raises a possibility that NF-E2-related factor 2 (Nrf2), which confers cytoprotection against oxidative stress, and p53 can have a direct co-regulation network. In the current study, we have indentified that the expression of murine double minute 2 (Mdm2) is repressed in nrf2-deleted murine embryonic fibroblasts (MEFs). This was confirmed by microarray, RT-PCR, and immunoblot analyses, and further promoter analysis showed that Nrf2 is directly involved in the basal expression of Mdm2 through the antioxidant response element, which is located in the first intron of this gene. This linkage between Nrf2 and Mdm2 appears to cause the accumulation of p53 protein in nrf2-deficent MEFs. In addition, we show that ovarian carcinoma A2780 cells with Nrf2 shRNA expression displayed higher levels of p53 activation in response to hydrogen peroxide treatment, leading to increased cell death. Collectively, our results suggest novel evidence that the inhibition of Nrf2 can suppress Mdm2 expression, which may result in p53 signaling modulation. In addition, this observation supports the concept that Nrf2 inhibition in cancer cells can facilitate apoptotic response upon environmental stress.