title: The accumulations of HIF-1α and HIF-2α by JNK and ERK are involved in biphasic effects induced by different levels of arsenite in human bronchial epithelial cells.
abstract: The biphasic effects of arsenite, in which low levels of arsenite induce cell proliferation and high levels of arsenite induce DNA damage and apoptosis, apparently contribute to arsenite-induced carcinogenesis. However, the mechanisms underlying this phenomenon are not well understood. In this study, we investigated the effects of different levels of arsenite on cell proliferation, DNA damage and apoptosis as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. Our results show that a low level of arsenite activates extracellular signal-regulated kinases (ERK), which probably mediate arsenite-inhibited degradation of ubiquitinated hypoxia-inducible factor-2α (HIF-2α) in HBE cells. ERK inhibition blocks cell proliferation induced by a low level of arsenite, in part via HIF-2α. In contrast, a high level of arsenite activates c-Jun N-terminal kinases (JNK), which provoke a response to suppress ubiquitinated HIF-1α degradation. Down-regulation of HIF-1α by inhibiting JNK, however, increases the DNA damage but decreases the apoptosis induced by a high level of arsenite. Thus, data in the present study suggest that the accumulations of HIF-1α and HIF-2α by JNK and ERK are involved in different levels of arsenite-induced biphasic effects, with low levels of arsenite inducing cell proliferation and high levels of arsenite inducing DNA damage and apoptosis in HBE cells.
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Huiqiao
authors.initials: H
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Pang
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rongrong
authors.initials: R
authors.lastname: Jiang
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhou
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.forename: Qizhan
authors.initials: Q
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000008:administration & dosage / Q000633:toxicity*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D018053:Arsenites; D051792:Basic Helix-Loop-Helix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D048031:JNK Mitogen-Activated Protein Kinases; D017670:Sodium Compounds; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C017947:sodium arsenite