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

Title
Transcription factor Nrf2 maintains the basal expression of Mdm2: An implication of the regulation of p53 signaling by Nrf2
Author(s)
곽미경Aram You[Aram You]Chang-won Nam[Chang-won Nam]Nobunao Wakabayashi[Nobunao Wakabayashi]Masayuki Yamamoto[Masayuki Yamamoto]Thomas W. Kensler[Thomas W. Kensler]
Keywords
CUL3-BASED E3 LIGASE; OXIDATIVE STRESS; ANTIOXIDANT RESPONSE; MOLECULAR-MECHANISMS; TUMOR-SUPPRESSOR; LUNG-CANCER; KEAP1; GENE; PATHWAY; IDENTIFICATION
Issue Date
201103
Publisher
ELSEVIER SCIENCE INC
Citation
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, v.507, no.2, pp.356 - 364
Abstract
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. (C) 2011 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/25540http://dx.doi.org/10.1016/j.abb.2010.12.034
ISSN
0003-9861
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약학대학 > 약학부 > Articles
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