https://scholars.lib.ntu.edu.tw/handle/123456789/392607
標題: | NcoA2-dependent inhibition of HIF-1α activation is regulated via AhR | 作者: | JAW-JOU KANG | 關鍵字: | Aryl hydrocarbon receptor (AhR); Benzo[a]pyrene (B[a]P); Hypoxia-inducible factor-1α (HIF-1α); Hypoxia-responsive element (HRE); Nuclear receptor coactivator 2 (NcoA2) | 公開日期: | 2015 | 卷: | 148 | 期: | 2 | 起(迄)頁: | 517-530 | 來源出版物: | Toxicological Sciences | 摘要: | High endogenous levels of aryl hydrocarbon receptor (AhR) contribute to hypoxia signaling pathway inhibition following exposure to the potent AhR ligand benzo[a]pyrene (B[a]P) and could alter cellular homeostasis and disease condition. Increasing evidence indicates that AhR might compete with AhR nuclear translocator (ARNT) for complex formation with hypoxia-inducible factor-1α (HIF-1α) for transactivation, which could alter several physiological variables. Nuclear receptor coactivator 2 (NcoA2) is a transcription coactivator that regulates transcription factor activation and inhibition of basic helix-loop-helix Per (Period)-ARNT-SIM (single-minded) (bHLH-PAS) family proteins, such as HIF-1α, ARNT, and AhR, through protein-protein interactions. In this study, we demonstrated that both hypoxia and hypoxia-mimic conditions decreased NcoA2 protein expression in HEK293T cells. Hypoxia response element (HRE) and xenobiotic-responsive element (XRE) transactivation also were downregulated with NcoA2 knockdown under hypoxic conditions. In addition, B[a]P significantly decreased NcoA2 protein expression be accompanied with AhR degradation. We next evaluated whether the absence of AhR could affect NcoA2 protein function under hypoxia-mimetic conditions. NcoA2 and HIF-1α nuclear localization decreased in both B[a]P-pretreated and AhR-knockdown HepG2 cells under hypoxia-mimic conditions. Interestingly, NcoA2 overexpression downregulated HRE transactivation by competing with HIF-1α and AhR to form protein complexes with ARNT. Both NcoA2 knockdown and overexpression inhibited endothelial cell tube formation in vitro. We also demonstrated using the in vivo plug assay that NcoA2-regulated vascularization decreased in mice. Taken together, these results revealed a biphasic role of NcoA2 between AhR and hypoxic conditions, thus providing a novel mechanism underlying the cross talk between AhR and hypoxia that affects disease development and progression. ? The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84952938759&partnerID=40&md5=1097e449f389cfeab43d3753175d03b5 http://scholars.lib.ntu.edu.tw/handle/123456789/392607 |
DOI: | 10.1093/toxsci/kfv199 | SDG/關鍵字: | aromatic hydrocarbon receptor; benzo[a]pyrene; cobalt chloride; hypoxia inducible factor 1; nuclear receptor coactivator 2; AHR protein, human; ARNT protein, human; aromatic hydrocarbon receptor; basic helix loop helix transcription factor; cobalt; cobalt chloride; HIF1A protein, human; hypoxia inducible factor 1alpha; hypoxia inducible factor 1beta; NCOA2 protein, human; nuclear receptor coactivator 2; oxygen; protein binding; animal experiment; animal model; Article; cell hypoxia; controlled study; DNA structure; down regulation; gene overexpression; homeostasis; human; human cell; hypoxia response element; mouse; nonhuman; nuclear localization signal; protein expression; signal transduction; transactivation; vascularization; xenobiotic responsive element; angiogenesis; animal; cell hypoxia; cell nucleus; dose response; drug effects; gene expression regulation; genetic transcription; genetic transfection; genetics; HEK293 cell line; HepG2 cell line; Institute for Cancer Research mouse; male; metabolism; RNA interference; transcription initiation; umbilical vein endothelial cell; xenograft; Animals; Aryl Hydrocarbon Receptor Nuclear Translocator; Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; Cell Nucleus; Cobalt; Dose-Response Relationship, Drug; Gene Expression Regulation; HEK293 Cells; Hep G2 Cells; Heterografts; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice, Inbred ICR; Neovascularization, Physiologic; Nuclear Receptor Coactivator 2; Oxygen; Protein Binding; Receptors, Aryl Hydrocarbon; RNA Interference; Signal Transduction; Transcription, Genetic; Transcriptional Activation; Transfection |
顯示於: | 毒理學研究所 |
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