title: Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.
abstract: 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.affiliation: The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Raju R
authors.initials: RR
authors.lastname: Raval
authors.forename: Kah Weng
authors.initials: KW
authors.lastname: Lau
authors.forename: Maxine G B
authors.initials: MG
authors.lastname: Tran
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Sowter
authors.forename: Stefano J
authors.initials: SJ
authors.lastname: Mandriota
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
mesh_terms: 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
chemical_list: 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