title: The Ras GTPase-activating-like protein IQGAP1 mediates Nrf2 protein activation via the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway.
abstract: Nrf2 plays a critical role in the regulation of cellular oxidative stress. MEK-ERK activation has been shown to be one of the major pathways resulting in the activation of Nrf2 and induction of Nrf2 downstream targets, including phase II detoxifying/antioxidant genes in response to oxidative stress and xenobiotics. In this study, IQGAP1 (IQ motif-containing GTPase-activating protein 1), a new Nrf2 interaction partner that we have published previously, was found to modulate MEK-ERK-mediated Nrf2 activation and induction of phase II detoxifying/antioxidant genes. Nrf2 binds directly to the IQ domain (amino acids 699-905) of IQGAP1. Knockdown of IQGAP1 significantly attenuated phenethyl isothiocyanate- or MEK-mediated activation of the MEK-ERK-Nrf2 pathway. Knockdown of IQGAP1 also attenuated MEK-mediated increased stability of Nrf2, which in turn was associated with a decrease in the nuclear translocation of Nrf2 and a decrease in the expression of phase II detoxifying/antioxidant genes. In the aggregate, these results suggest that IQGAP1 may play an important role in the MEK-ERK-Nrf2 signaling pathway.
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Ka Lung
authors.initials: KL
authors.lastname: Cheung
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Lee
authors.forename: Limin
authors.initials: L
authors.lastname: Shu
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: David B
authors.initials: DB
authors.lastname: Sacks
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020703:ras GTPase-Activating Proteins / Q000502:physiology*
chemical_list: D017931:DNA Primers; C101203:IQ motif containing GTPase activating protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020703:ras GTPase-Activating Proteins
keywords: Antioxidants; ERK; Gene Silencing; IQGAP1; MEK; Nrf2; PEITC; Scaffold Proteins