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dc.contributor.authorRaval, RRen
dc.contributor.authorLau, KWen
dc.contributor.authorTran, MGBen
dc.contributor.authorSowter, HMen
dc.contributor.authorMandriota, SJen
dc.contributor.authorLi, J-Len
dc.contributor.authorPugh, CWen
dc.contributor.authorMaxwell, PHen
dc.contributor.authorHarris, ALen
dc.contributor.authorRatcliffe, PJen
dc.date.accessioned2017-11-27T16:30:28Z
dc.date.available2017-11-27T16:30:28Z
dc.date.issued2005-07en
dc.identifier.issn0270-7306en
dc.identifier.urihttp://hdl.handle.net/10026.1/10307
dc.description.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.

en
dc.format.extent5675 - 5686en
dc.languageengen
dc.language.isoengen
dc.subjectAmino Acid Sequenceen
dc.subjectAnimalsen
dc.subjectBasic Helix-Loop-Helix Transcription Factorsen
dc.subjectCarcinoma, Renal Cellen
dc.subjectCell Line, Tumoren
dc.subjectCyclin Den
dc.subjectCyclinsen
dc.subjectDNA-Binding Proteinsen
dc.subjectGenes, Tumor Suppressoren
dc.subjectHumansen
dc.subjectHypoxia-Inducible Factor 1en
dc.subjectHypoxia-Inducible Factor 1, alpha Subuniten
dc.subjectImmunohistochemistryen
dc.subjectKidney Neoplasmsen
dc.subjectMiceen
dc.subjectMice, Nudeen
dc.subjectMutationen
dc.subjectNeoplasm Transplantationen
dc.subjectNuclear Proteinsen
dc.subjectProtein Structure, Tertiaryen
dc.subjectRNA, Small Interferingen
dc.subjectRetroviridaeen
dc.subjectTranscription Factorsen
dc.subjectTransforming Growth Factor alphaen
dc.subjectTransplantation, Heterologousen
dc.subjectVascular Endothelial Growth Factor Aen
dc.subjectvon Hippel-Lindau Diseaseen
dc.titleContrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.en
dc.typeJournal Article
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/15964822en
plymouth.issue13en
plymouth.volume25en
plymouth.publication-statusPublisheden
plymouth.journalMol Cell Biolen
dc.identifier.doi10.1128/MCB.25.13.5675-5686.2005en
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine/UoA01 Clinical Medicine
dc.publisher.placeUnited Statesen
dc.rights.embargoperiodNot knownen
rioxxterms.versionofrecord10.1128/MCB.25.13.5675-5686.2005en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.typeJournal Article/Reviewen


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