- Paper Report
- Open Access
Targeting the HIF system
- Oliver Distler1
© Biomed Central Ltd 2001
- Published: 1 February 2001
Cellular hypoxia is a hallmark of many tumors and is involved in key aspects of tumor biology such as angiogenesis, invasion and altered energy metabolism through induction of the transcription factor hypoxia inducible factor-1 (HIF-1). The aim of the present study was to investigate whether inhibition of the HIF-1 pathway can reduce tumor growth.
Interaction of the HIF heterodimer with the p300/CBP coactivator is essential for transactivation of HIF-1 regulated genes such as insulin-like growth factor-2, transforming growth factor-?3, vascular endothelial growth factor (VEGF) and the VEGF receptor FLT-1. Transfection of Hep3B cells with expression plasmids for polypeptides corresponding to the p300/CBP-binding domain of HIF-1a resulted in a significant attenuation of hypoxia-inducible reporter activity due to competitive binding inhibition. When hepatoma cells were infected with retroviruses encoding these polypeptides, VEGF mRNA abundance was reproducibly reduced. To assess the effects of HIF-1 blockade in vivo, retrovirally infected tumor cells were implanted into nude mice. Tumor growth and vessel density were reduced compared to values in control experiments.
In vitro protein binding assays, luciferase reporter assays, ssDNA mutagenesis, thioredoxin-constrained expression vectors, immunoblot, ribonuclease protection, xenograft nude mice tumor model
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