title: Regulation of hemeoxygenase-1 gene expression by Nrf2 and c-Jun in tertiary butylhydroquinone-stimulated rat primary astrocytes.
abstract: Hemeoxygenase-1 (HO-1) is a phase II antioxidant enzyme that is primarily involved in detoxification and cytoprotection in a variety of tissues. However, the mechanism underlying HO-1 gene expression remains unclear. In the present study, we investigated the regulation of HO-1 expression in primary cultured astrocytes by using the natural antioxidant compound tertiary butylhydroquinone (tBHQ). We found that tBHQ increased HO-1 mRNA and protein levels. Promoter analysis revealed that tBHQ enhanced HO-1 gene transcription in an antioxidant response element (ARE)-dependent manner. In addition, tBHQ increased the nuclear translocation and DNA binding of Nrf2 and c-Jun to ARE. Small interfering RNA (siRNA) experiments demonstrated that Nrf2 and c-Jun are involved in the differential modulation of HO-1 expression. Thus, Nrf2 knockdown reduced the basal level of HO-1 expression but did not affect the fold induction by tBHQ. On the other hand, knockdown of c-Jun diminished tBHQ-mediated induction of HO-1 without affecting basal expression. The data suggest that Nrf2 generally modulates the basal expression of HO-1, while c-Jun mediates HO-1 induction in response to tBHQ. The results of co-immunoprecipitation assays demonstrated a physical interaction between Nrf2 and c-Jun in tBHQ-treated astrocytes. The results suggest that Nrf2 and c-Jun regulate HO-1 expression via their coordinated interaction in tBHQ-treated rat primary astrocytes.
authors.affiliation: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea. Electronic address: hskimp@ewha.ac.kr.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D006873:Hydroquinones / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats
chemical_list: D000975:Antioxidants; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C018855:2-tert-butylhydroquinone; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat
keywords: Astrocyte; Gene regulation; Hemeoxygenase-1; Nrf2; c-Jun; tBHQ