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Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.
MOL CELL BIOL
5675 - 5686.
Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1 alpha and HIF-2 alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1 alpha and HIF-2 alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-alpha isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2 alpha suppressing HIF-1 alpha and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2 alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1 alpha and negatively to HIF-2 alpha, indicating that HIF-1 alpha and HIF-2 alpha have contrasting properties in the biology of RCC. In keeping with this, HIF-alpha isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1 alpha retarding and HIF-2 alpha enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.
|Title:||Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma|
|Keywords:||TUMOR-SUPPRESSOR PROTEIN, PAS DOMAIN PROTEIN-1, GENE-EXPRESSION, CYCLIN D1, FACTOR (HIF)-1-ALPHA, FACTOR 1-ALPHA, TARGET GENE, HIF-1-ALPHA, CANCER, GROWTH|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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