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

Journal Article · Tue Jan 15 04:00:00 EST 2013 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2012.11.014· OSTI ID:22216032

Xu, Yuan; Li, Yuan ^[1]; Li, Huiqiao ^[2]; Pang, Ying; Zhao, Yue; Jiang, Rongrong; Shen, Lu ^[1]; Zhou, Jianwei; Wang, Xinru ^[3]; Liu, Qizhan ^[1]

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1. Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu (China)
2. Qujing Center for Disease Control and Prevention, Qujing 655000, Yunnan (China)
3. The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu (China)

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. -- Highlights: ► Biphasic effects induced by different concentrations of arsenite. ► Different regulation of ERK or JNK signal pathway by arsenite. ► Different regulation of HIF1α or HIF 2α by arsenite.

• OSTI ID: 22216032
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 266; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANOXIA
APOPTOSIS
CARCINOGENESIS
CELL PROLIFERATION
CONCENTRATION RATIO
DNA DAMAGES
PHOSPHOTRANSFERASES