Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.
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.
Raval
Raju R
RR
The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
Lau
Kah Weng
KW
Tran
Maxine G B
MG
Sowter
Heidi M
HM
Mandriota
Stefano J
SJ
Li
Ji-Liang
JL
Pugh
Christopher W
CW
Maxwell
Patrick H
PH
Harris
Adrian L
AL
Ratcliffe
Peter J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000276:immunology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000276:immunology; D006623:von Hippel-Lindau Disease / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D056741:Cyclin D; D016213:Cyclins; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse