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Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha 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-2alpha suppressing HIF-1alpha 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-2alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1alpha and negatively to HIF-2alpha, indicating that HIF-1alpha and HIF-2alpha 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-1alpha retarding and HIF-2alpha 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.

Original publication

DOI

10.1128/MCB.25.13.5675-5686.2005

Type

Journal article

Journal

Mol cell biol

Publication Date

07/2005

Volume

25

Pages

5675 - 5686

Keywords

Amino Acid Sequence, Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Line, Tumor, Cyclin D, Cyclins, DNA-Binding Proteins, Genes, Tumor Suppressor, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunohistochemistry, Kidney Neoplasms, Mice, Mice, Nude, Mutation, Neoplasm Transplantation, Nuclear Proteins, Protein Structure, Tertiary, RNA, Small Interfering, Retroviridae, Transcription Factors, Transforming Growth Factor alpha, Transplantation, Heterologous, Vascular Endothelial Growth Factor A, von Hippel-Lindau Disease