Abstract
Nuclear factor Nrf 2, under normal conditions, is retained in the cytosol by INrf 2. Antioxidants and oxidants antagonize this interaction, resulting in the release of Nrf 2. Nrf 2 translocates to the nucleus binds to ARE and activates a battery of chemopreventive genes. Once this is achieved, Nrf 2 is exported out of the nucleus, binds with INrf 2, and degrades. Nrf 2 contains well defined signals that control nuclear import and export of Nrf 2. The present studies demonstrate that phosphorylation of tyrosine 568 is required for Crm1-mediated nuclear export and degradation of Nrf 2. Mutation of tyrosine 568 to alanine and phenylalanine resulted in the loss of interaction with Crm1 and abrogation of nuclear export of Nrf 2. Nrf 2Y568A is deficient in nuclear export and displays delayed degradation compared with wild-type Nrf 2. In addition, Src inhibitor PP2 caused nuclear accumulation of Nrf 2 in normal and hydrogen peroxide-treated cells but had no effect on localization of mutant Nrf 2Y568A. Further experiments with small interfering RNA revealed that Fyn phosphorylated Nrf 2Y568 leading to nuclear export and degradation of Nrf 2.
Highlights
Interaction with Crm1 and abrogation of nuclear export of Nrf 2
Genistein treatment caused nuclear accumulation of Nrf2 as ϳ80% of cells displayed Nrf2 to be accumulated in the nucleus (Fig. 1C, the graph in the right panel). These results suggested that Nrf2 might be phosphorylated by tyrosine kinase(s) and that inhibition of tyrosine phosphorylation resulted in increased concentration of Nrf2 in the nucleus
PP2 blocked the tyrosine phosphorylation of Nrf2 at 2 h of hydrogen peroxide treatment (Fig. 4C). These results suggested that hydrogen peroxide-induced nuclear export of Nrf2 is mediated via tyrosine phosphorylation of Nrf2 by Src kinase(s)
Summary
Interaction with Crm and abrogation of nuclear export of Nrf 2. Src inhibitor proteins and increased sensitivity to oxidative stress [11]. PP2 caused nuclear accumulation of Nrf 2 in normal and hydrogen gested that Nrf accumulation in nucleus because of disruption of INrf peroxide-treated cells but had no effect on localization of mutant leads to adverse effects on cell growth and survival. Nlinrfg bcianndsoccBuarc.h1T:hMeaffGig; uMreafGd/oKe/sF:MnoatfGs/uKp/Fp,ocr-tJun:c-Fos, and c-Jun-Fra, preto antioxidant response eletmheantt t(hAeRrEe) aisndnoreglaublaetelsinegxparfetsesirontraanndsfescutmioanblwy tiothrapthidelyebmrinpgtdyowpcnDthNeAindvueccetdoArRE-mediated gene exprescoordinated induction of a baatntedrythofegecnlaesimencthodaitngtrcahnemsfoepcrteivoenntiwveith stihoen taocntoivrme aclolenvsetlsr.uRcetcsenhtlayd, staudsipesehcaifviecdemonstrated that INrf is proteins, including detoxifyingeenffzeymcte.sTNhAeDi(nP)vHe:qstuiignoanteioonxidaolsreodudcetat-ermalisnoelodcathlizaetdiinn Fthige.n6u,clienusthpreesvuemrasbiolyntso degrade Nrf2 [13, 14].
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