title: Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia.
abstract: Hypoxia-inducible factors (HIFs) play key roles in the cellular response to hypoxia. It is widely accepted that whereas HIF-1 and HIF-2 function as transcriptional activators, HIF-3 inhibits HIF-1/2α action. Contrary to this idea, we show that zebrafish Hif-3α has strong transactivation activity. Hif-3α is degraded under normoxia. Mutation of P393, P493, and L503 inhibits this oxygen-dependent degradation. Transcriptomics and chromatin immunoprecipitation analyses identify genes that are regulated by Hif-3α, Hif-1α, or both. Under hypoxia or when overexpressed, Hif-3α binds to its target gene promoters and upregulates their expression. Dominant-negative inhibition and knockdown of Hif-3α abolish hypoxia-induced Hif-3α-promoter binding and gene expression. Hif-3α not only mediates hypoxia-induced growth and developmental retardation but also possesses hypoxia-independent activities. Importantly, transactivation activity is conserved and human HIF-3α upregulates similar genes in human cells. These findings suggest that Hif-3 is an oxygen-dependent transcription factor and activates a distinct transcriptional response to hypoxia.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Po-Ju
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: cduan@umich.edu.
authors.forename: Cunming
authors.initials: C
authors.lastname: Duan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015027:Zebrafish
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C116973:HIF3A protein, human