Targeted Replacement of Hypoxia-Inducible Factor-1{alpha} by a Hypoxia-Inducible Factor-2{alpha} Knock-in Allele Promotes Tumor Growth

doi:10.1158/0008-5472.CAN-04-3246

Cell and Tumor Biology

Targeted Replacement of Hypoxia-Inducible Factor-1 ${alpha}$ by a Hypoxia-Inducible Factor-2 ${alpha}$ Knock-in Allele Promotes Tumor Growth

Kelly L. Covello¹, M. Celeste Simon¹^,2^,3 and Brian Keith²

¹ Department of Cell and Developmental Biology, ² Abramson Family Cancer Research Institute, and ³ Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: M. Celeste Simon, Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III, Room 450, Philadelphia, PA 19104. Phone: 215-746-5526; Fax: 215-746-5561; E-mail: celeste2{at}mail.med.upenn.edu.

Hypoxia-inducible factors (HIF) are essential transcriptionalregulators that mediate adaptation to hypoxic stress in rapidlygrowing tissues such as tumors. HIF activity is regulated byhypoxic stabilization of the related HIF-1 ${alpha}$ and HIF-2 ${alpha}$ subunits,which are frequently overexpressed in cancer cells. To assessthe relative tumor-promoting functions of HIF-1 ${alpha}$ and HIF-2 ${alpha}$ directly,we replaced HIF-1 ${alpha}$ expression with HIF-2 ${alpha}$ by creating a novel"knock-in" allele at the Hif-1 ${alpha}$ locus through homologous recombinationin primary murine embryonic stem cells. Compared with controls,s.c. teratomas derived from knock-in embryonic stem cells werelarger and more proliferative, had increased microvessel density,and exhibited increased expression of vascular endothelial growthfactor, transforming growth factor- ${alpha}$ , and cyclin D1. These andother data indicate that HIF-2 ${alpha}$ promotes tumor growth more effectivelythan HIF-1 ${alpha}$ in multiple contexts.

Key Words: HIF • Hypoxia • VEGF • angiogenesis

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