Role of the Redox-Sensitive Transcription Factor, Nuclear Factor E2-Related Factor-2 in Adaptive Cellular Stress Response

다국어 초록 (Multilingual Abstract)

The induction of antioxidant enzyme gene expression represents the first line of cellular defence against oxidative/nitrosative stress and other noxious stimuli. Experimental models of various diseases including acute inflammation, atherosclerosis, neurodegenerative disorders and cancer have demonstrated that the induction of heme oxygenase-1(HO-1) can prevent or mitigate the symptoms associated with these ailments. Nuclear factor E2-related factor-2(Nrf2) has been identified as a major transcription factor responsible for regulating expression of HO-1 and other antioxidant enzymes. Our recent studies have demonstrated that peroxynitrite induces HO-1 expression and subsequently glutamate cysteine ligase(GCLC) through activation of Nrf2 signaling, which confers the cellular protection or tolerance against the subsequent injuries. HO-1 induction was also associated with cytoprotection against inflammatory tissue injuries. Some chemopreventive and chemoprotective phytochemicals, such as curcumin, zerumbone, resveratrol, the green tea polyphenol EGCG, sulforaphane and capsaicin, induce HO-1 expression via Nrf2 activation. Nrf2 knock out mice were less responsive to HO-1 induction following administration of some of these phytochemicals and more prone to inflammatory as well as oxidative or nitrosative stress. Recent studies have revealed that cysteine thiols present in Keap1, a negative regulator of Nrf2, function as redox sensors in fine-tuning of transcriptional regulation of Nrf2. Certain chemopreventive and cytoprotective agents as well as electrophiles and prooxidants can oxidize or covalently modify critical cysteine thiols present in Keap1, thereby diminishing the affinity of Keap1 for Nrf2. This leads to release of Nrf2 for translocation to nucleus where it binds to antioxidant response elements, potentiating cellular defence signaling.