title: Hypoxia-inducible factor 1α mediates the down-regulation of superoxide dismutase 2 in von Hippel-Lindau deficient renal clear cell carcinoma.
abstract: Hypoxia-inducible factor 1α (HIF-1α) is an oxygen-sensitive subunit of HIF-1, the master transcription factor for cellular response to hypoxia. Down-regulation of the mitochondrial enzyme superoxide dismutase 2 (SOD2) contributes to the stabilization of HIF-1α under hypoxia due to the decreased dismutation of superoxide radical. Here we report that HIF-1α could also regulate the expression of SOD2. We found that both stabilization of HIF-1α expression under nomoxia caused by pVHL deficiency and hypoxia treatment significantly reduced SOD2 expression, and shRNAs specifically against HIF-1α restored SOD2 expression in both circumstances. Further analyses with luciferase reporter assay and chromatin immunoprecipitation assay revealed that HIF-1α inhibited and directly bound to the hypoxia-responsive element in SOD2 promoter. These findings indicated the existence of a positive feedback between HIF-1α and SOD2 and provided new clues for understanding the molecular mechanisms of hypoxia adaptation.
authors.affiliation: Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiaotong University School of Medicine (SJTU-SM), Shanghai 200025, PR China.
authors.forename: Yao-Hui
authors.initials: YH
authors.lastname: Gao
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Li
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Shen
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Wei
authors.forename: Li-Shun
authors.initials: LS
authors.lastname: Wang
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013482:Superoxide Dismutase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099156:Superoxide Dismutase 2; C497446:VHL protein, human