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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006376-03
Application #
2155241
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1993-06-01
Project End
1997-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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