HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.

Authors:
Kelly L Covello
Kelly L Covello
University of Pennsylvania School of Medicine
United States
James Kehler
James Kehler
Veterinary Bioscience Institute
United States
Hongwei Yu
Hongwei Yu
Joan C. Edwards School of Medicine at Marshall University
United States
John D Gordan
John D Gordan
University of California
Berkeley | United States
Andrew M Arsham
Andrew M Arsham
University of Minnesota
United States
Dr. Cheng-Jun Hu, PhD
Dr. Cheng-Jun Hu, PhD
University of Colorado
Associate Professor
Pulmonary hypertension
Aurora, CO | United States
Patricia A Labosky
Patricia A Labosky
University of Pennsylvania School of Medicine
United States

Genes Dev 2006 Mar;20(5):557-70

Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

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.

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Source
http://dx.doi.org/10.1101/gad.1399906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1410808PMC
March 2006
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241 Citations
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