title: Hypoxia-inducible factor 1 regulated ARC expression mediated hypoxia induced inactivation of the intrinsic death pathway in p53 deficient human colon cancer cells.
abstract: Apoptosis repressor with caspase recruitment domain (ARC), an anti-apoptotic protein, plays an important role in the regulation of apoptosis by blocking both the extrinsic and intrinsic death pathways. However, its regulatory mechanism remains largely undefined. Here, we reported that hypoxia up-regulated the expression of ARC in p53 deficient human colon cancer cells. Moreover, ARC is a direct target of the hypoxia-inducible factor 1 (HIF-1), a key transcriptional factor for the cellular response to hypoxia. Silencing the expression of HIF-1α in SW480 colon cancer cells by RNA interference abolished hypoxia induced ARC expression. Using luciferase reporter and ChIP assay, we showed that HIF-1α directly bound to hypoxia-responsive element located at -419 to -414 of ARC gene, which is essential for HIF-1-induced expression. As a result of the increased ARC expression, TRAIL-induced apoptosis was reduced by hypoxia. These discoveries would shed novel insights on the mechanisms for ARC expression regulation and hypoxia induced inactivation of the intrinsic death pathway.
authors.affiliation: Department of Pathology, Jingmen Hubei Province First Peoples' Hospital, Jingmen, Hubei, China.
authors.forename: Jin-e
authors.initials: JE
authors.lastname: Ao
authors.forename: Liang-hong
authors.initials: LH
authors.lastname: Kuang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rong
authors.initials: R
authors.lastname: Zhao
authors.forename: Chang-ming
authors.initials: CM
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D051793:Hypoxia-Inducible Factor 1; D009124:Muscle Proteins; C112246:NOL3 protein, human; D016159:Tumor Suppressor Protein p53