Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.

Journal article

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.

Authors: Raval, R; Lau, K; Tran, MG; Sowter, H; Mandriota, S

• Publication status: Published
• Journal: Molecular and cellular biology
• Volume: 25
• Issue: 13
• Pages: 5675-5686
• Publication date: 2005-07-01
• DOI: 10.1128/mcb.25.13.5675-5686.2005
• EISSN: 1098-5549
• ISSN: 0270-7306
• Language: English
• Keywords: Carcinoma, Renal Cell; von Hippel-Lindau Disease; Hypoxia-Inducible Factor 1; Retroviridae; Transplantation, Heterologous; Hypoxia-Inducible Factor 1, alpha Subunit; Humans; Basic Helix-Loop-Helix Transcription Factors; Nuclear Proteins; Mice; Amino Acid Sequence; Neoplasm Transplantation; Transcription Factors; Cyclins; Vascular Endothelial Growth Factor A; Animals; Genes, Tumor Suppressor; Cell Line, Tumor; Transforming Growth Factor alpha; Cyclin D; DNA-Binding Proteins; Kidney Neoplasms; Protein Structure, Tertiary; Mutation; Mice, Nude; RNA, Small Interfering; Immunohistochemistry