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Vol. 62, Issue 5, 1001-1010, November 2002
College of Pharmacy and Research Institute of Pharmaceutical
Sciences, Seoul National University, Seoul, South Korea
Expression of phase II detoxifying genes is regulated by
NF-E2-related factor 2 (Nrf2)-mediated antioxidant response element (ARE) activation. We showed previously that phosphatidylinositol 3 (PI3)-kinase plays an essential role in ARE-mediated rGSTA2 induction
by oxidative stress. In view of the fact that the signaling pathway of
PI3-kinase controls microfilaments and translocation of
actin-associated proteins, the current study was designed to investigate the PI3-kinase-mediated nuclear translocation of Nrf2 and
the interaction of Nrf2 with actin.
tert-Butylhydroquinone (t-BHQ) caused
Nrf2 to translocate into the nucleus in H4IIE cells, which was
prevented by pretreatment of the cells with PI3-kinase inhibitors
(wortmannin/LY294002). t-BHQ relocalized Nrf2 in concert with changes in actin microfilament architecture, as visualized by
superposition of immunochemically stained Nrf2 and fluorescent phalloidin-stained actin. Furthermore, t-BHQ increased
the level of nuclear actin, coimmunoprecipitated with Nrf2, which
returned to that of control by pretreatment of the cells with
PI3-kinase inhibitors. Cytochalasin B, an actin disruptor, alone
stimulated actin-mediated nuclear translocation of Nrf2 and induced
rGSTA2. In contrast, phalloidin, an agent that prevents actin filaments from depolymerization, inhibited Nrf2 translocation and rGSTA2 induction by t-BHQ. Subcellular fractionation and
immunoblot analyses allowed us to detect both 57- and 100-kDa Nrf2.
Immunoblot and immunoprecipitation assays showed that the 100-kDa
protein comprised both Nrf2 and actin. The present study demonstrates
that the PI3-kinase signaling pathway regulates rearrangement of actin
microfilaments in response to oxidative stress and that
depolymerization of actin causes a complex of Nrf2 bound with actin to
translocate into nucleus.
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