Presentation
# 2
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6th Internet World Congress for Biomedical Sciences |
S. Dhakshinamoorthy(1), D. Bloom(2), Anil Jaiswal(3)
(1)(2)Department of Pharmacology. Baylor College of Medicine. - Houston. United States
(3)Baylor College of Medicine - Houston. United States
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Antioxidants are substances that delay or prevent the oxidation of cellular oxidizable substrates. The various antioxidants exert their effect by scavenging superoxide, or by activating of a battery of detoxifying/defensive proteins. In this article, we have focused on the mechanisms by which antioxidant induce gene expression. Many xenobiotics (e. g. b-naphthoflavone) activate the similar genes as antioxidants. The promoters of these genes contain a common cis-element designated as ´Antioxidant Response Element´ or ´ARE´. The ARE contains two TRE (TPA response element) or TRE-like elements followed by ´GC´ box. Mutational studies identified GTGAC***GC as core of the ARE sequence. Many transcription factors including Nrf, Jun, Fos, Fra, Maf, YABP, ARE-BP1, Ah (aromatic hydrocarbon) receptor and estrogen receptor bind to the ARE from the various genes. Among these factors, Nrf-Jun heterodimers positively regulate ARE-mediated expression and induction of genes in response to antioxidants and xenobiotics. This Nrf-Jun heterodimerization and binding to the ARE requires unknown cytosolic factors.
The mechanism of signal transduction from antioxidants and xenobiotics includes several steps, 1) Antioxidants and xenobiotics undergo metabolism to generate superoxide and related reactive species leading to the generation of a signal to activate detoxifying/defensive genes expression; 2) The generation of superoxide and related reactive species is followed by activation of yet to be identified cytosolic factor(s), by unknown mechanism(s); 3). Activated cytosolic factor(s) catalyze modification of Nrf2 and/or INrf2 4) Release of Nrf2 from INrf2 followed by nuclear localization of Nrf2 to the nucleus; 5) Transcriptional activation and modification? of c-Jun; 6) Heterodimerization of Nrf2 with c-Jun; 7) Binding of Nrf2-c-Jun complex to the ARE from the various detoxifying enzyme genes; and 8) The coordinated increased transcription of genes encoding detoxifying/defensive proteins. In this mechanism Nrf1 is expected to behave same as Nrf2 and Jun-B and Jun-D proteins same as c-Jun. The unknown cytosolic factor(s) are significant molecules because they represent the oxidative sensors within the cells. Identification of the cytosolic factor(s) will be of considerable importance in the field of antioxidants and gene regulation research. Future studies will also be required to completely understand the molecular mechanism of signal transduction from antioxidants and xenobiotics to Nrf-Jun. In addition to Nrf-Jun pathway, the mammalian cells also contain other pathways that activate gene expression in response to oxidative stress. These include NF-KB, HIF-1 Mac-1 and SRF mediated pathways. It is expected that collectively these pathways increase transcription of more than four dozen genes to protect cells against oxidative stress.
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