title: HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.
abstract: The division, differentiation, and function of stem cells and multipotent progenitors are influenced by complex signals in the microenvironment, including oxygen availability. Using a genetic "knock-in" strategy, we demonstrate that targeted replacement of the oxygen-regulated transcription factor HIF-1alpha with HIF-2alpha results in expanded expression of HIF-2alpha-specific target genes including Oct-4, a transcription factor essential for maintaining stem cell pluripotency. We show that HIF-2alpha, but not HIF-1alpha, binds to the Oct-4 promoter and induces Oct-4 expression and transcriptional activity, thereby contributing to impaired development in homozygous Hif-2alpha KI/KI embryos, defective hematopoietic stem cell differentiation in embryoid bodies, and large embryonic stem cell (ES)-derived tumors characterized by altered cellular differentiation. Furthermore, loss of HIF-2alpha severely reduces the number of embryonic primordial germ cells, which require Oct-4 expression for survival and/or maintenance. These results identify Oct-4 as a HIF-2alpha-specific target gene and indicate that HIF-2alpha can regulate stem cell function and/or differentiation through activation of Oct-4, which in turn contributes to HIF-2alpha's tumor promoting activity.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Covello
authors.forename: James
authors.initials: J
authors.lastname: Kehler
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yu
authors.forename: John D
authors.initials: JD
authors.lastname: Gordan
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Arsham
authors.forename: Cheng-Jun
authors.initials: CJ
authors.lastname: Hu
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Labosky
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
mesh_terms: D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D013724:Teratoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050814:Octamer Transcription Factor-3; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1