Exposure of mammalian cells to redox active xenobiotics, such as quinoid compounds, leads to considerable structural damage as well as carcinogenesis. A certain degree of protection against such substances is offered by induction of phase II xenobiotic metabolizing enzymes such as quinone reductase (QR) and glutathione S-transferase (GST). This induction occurs at the transcriptional level and is mediated through a common cis acting element present in the promoters of both the QR and GST-Ya subunit genes, termed either ARE (antioxidant response element) of ERE (electrophile response element). The ARE/ERE sequence shows considerable similarity to the consensus sequence recognized by AP-1, a sequence specific transcription factor composed of Jun and Fos proteins. In fact, AP-1 binds to the various ARE/ERE sequences and its activity is induced in response to oxidative stress. We propose that AP-1 serves a second prototype of xenobiotic """"""""receptor"""""""". Unlike the classical Ah receptor, AP-1 activity is not regulated by direct binding of xenobiotics. A likely mechanism that controls AP-1 activity involves a signal transduction cascade that is initiated by free radicals that are produced as a result of exposure to redox active xenobiotics. to test this hypothesis and determine the mechanisms by which electrophilic xenobiotics stimulate AP-1 activity, we propose to: 1) determine the composition of the AP-1 complex that interacts with the ARE/EREs; 2) determine whether redox active xenobiotics stimulate AP-1 activity by transcriptional or post-translational mechanisms; 3) analyze changes in Jun protein phosphorylation in response to xenobiotic exposure; 4) examine the induction of c-jun transcription by xenobiotics and determine the xenobiotic response element in the c-jun promoter; 5) examine the involvement of tyrosine kinases, Ha-Ras and Raf-1 proteins in the signal transduction pathway leading to gene induction through ARE/ERE and increased AP-1 activity; 6) examine the effect of xenobiotics on tyrosine phosphorylation and the activity of tyrosine kinases; 7) examine whether xenobiotics lead to inhibition of tyrosine phosphatases via free radical production. These studies should provide a detailed molecular understanding of the mechanisms by which redox active xenobiotics affect gene expression and act as tumor promoters.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Chemical Pathology Study Section (CPA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Sakurai, Toshiharu; Kudo, Masatoshi; Umemura, Atsushi et al. (2013) p38? inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res 73:215-24
Du, Hongjun; Sun, Xufang; Guma, Monica et al. (2013) JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Natl Acad Sci U S A 110:2377-82
Lee, Jun Hee; Budanov, Andrei V; Talukdar, Saswata et al. (2012) Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab 16:311-21
Guma, Monica; Hammaker, Deepa; Topolewski, Katharyn et al. (2012) Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6. Arthritis Rheum 64:2887-95
Aghajan, Mariam; Li, Ning; Karin, Michael (2012) Obesity, autophagy and the pathogenesis of liver and pancreatic cancers. J Gastroenterol Hepatol 27 Suppl 2:10-4
Sun, Beicheng; Karin, Michael (2012) Obesity, inflammation, and liver cancer. J Hepatol 56:704-13
Ali, Syed Raza; Timmer, Anjuli M; Bilgrami, Sameera et al. (2011) Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage. Immunity 35:34-44
Holzer, Ryan G; Park, Eek-Joong; Li, Ning et al. (2011) Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 147:173-84
Lee, Jun Hee; Budanov, Andrei V; Park, Eek Joong et al. (2010) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327:1223-8
Budanov, Andrei V; Lee, Jun Hee; Karin, Michael (2010) Stressin' Sestrins take an aging fight. EMBO Mol Med 2:388-400

Showing the most recent 10 out of 54 publications