title: Hydroquinone regulates hemeoxygenase-1 expression via modulation of Src kinase activity through thiolation of cysteine residues.
abstract: The hydroxylated benzene metabolite hydroquinone (HQ) is mainly generated from benzene, an important industrial chemical, and is also a common dietary component. Although numerous papers have addressed the potential role of HQ in tumorigenic responses, the immunosuppressive and anti-inflammatory effects of hydroquinone have also been considered. In this study, we characterized the mechanism of the induction of hemeoxygenase (HO)-1 and other phase 2 enzymes by HQ and its derivatives. HQ upregulated the mRNA and protein levels of HO-1 by increasing the antioxidant-response element-dependent transcriptional activation of Nrf-2. Src knockdown or deficiency induced via siRNA treatment and infection with a retrovirus expressing shRNA targeting Src, as well as exposure to PP2, a Src kinase inhibitor, strongly abrogated HO-1 expression. Interestingly, HQ directly targeted and bound to the sulfhydryl group of cysteine-483 (C483) and C400 residues of Src, potentially leading to disruption of intracellular disulfide bonds. Src kinase activity was dramatically enhanced by mutation of these cysteine sites, implying that these sites may play an important role in the regulation of Src kinase activity. Therefore, our data suggest that Src and, particularly, its C483 target site can be considered as prime molecular targets of the HQ-mediated induction of phase 2 enzymes, which is potentially linked to HO-1-mediated cellular responses such as immunosuppressive and anti-inflammatory actions.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 446-746, Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Byeon
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yang
authors.forename: Yong Gyu
authors.initials: YG
authors.lastname: Lee
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Jueun
authors.initials: J
authors.lastname: Oh
authors.forename: Hye Yoon
authors.initials: HY
authors.lastname: Jeong
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D007249:Inflammation; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D003545:Cysteine; C031927:hydroquinone