HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.
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.
Covello
Kelly L
KL
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Kehler
James
J
Yu
Hongwei
H
Gordan
John D
JD
Arsham
Andrew M
AM
Hu
Cheng-Jun
CJ
Labosky
Patricia A
PA
Simon
M Celeste
MC
Keith
Brian
B
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
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