Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.
dc.contributor.author | Raval, RR | en |
dc.contributor.author | Lau, KW | en |
dc.contributor.author | Tran, MGB | en |
dc.contributor.author | Sowter, HM | en |
dc.contributor.author | Mandriota, SJ | en |
dc.contributor.author | Li, J-L | en |
dc.contributor.author | Pugh, CW | en |
dc.contributor.author | Maxwell, PH | en |
dc.contributor.author | Harris, AL | en |
dc.contributor.author | Ratcliffe, PJ | en |
dc.date.accessioned | 2017-11-27T16:30:28Z | |
dc.date.available | 2017-11-27T16:30:28Z | |
dc.date.issued | 2005-07 | en |
dc.identifier.issn | 0270-7306 | en |
dc.identifier.uri | http://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.extent | 5675 - 5686 | en |
dc.language | eng | en |
dc.language.iso | eng | en |
dc.subject | Amino Acid Sequence | en |
dc.subject | Animals | en |
dc.subject | Basic Helix-Loop-Helix Transcription Factors | en |
dc.subject | Carcinoma, Renal Cell | en |
dc.subject | Cell Line, Tumor | en |
dc.subject | Cyclin D | en |
dc.subject | Cyclins | en |
dc.subject | DNA-Binding Proteins | en |
dc.subject | Genes, Tumor Suppressor | en |
dc.subject | Humans | en |
dc.subject | Hypoxia-Inducible Factor 1 | en |
dc.subject | Hypoxia-Inducible Factor 1, alpha Subunit | en |
dc.subject | Immunohistochemistry | en |
dc.subject | Kidney Neoplasms | en |
dc.subject | Mice | en |
dc.subject | Mice, Nude | en |
dc.subject | Mutation | en |
dc.subject | Neoplasm Transplantation | en |
dc.subject | Nuclear Proteins | en |
dc.subject | Protein Structure, Tertiary | en |
dc.subject | RNA, Small Interfering | en |
dc.subject | Retroviridae | en |
dc.subject | Transcription Factors | en |
dc.subject | Transforming Growth Factor alpha | en |
dc.subject | Transplantation, Heterologous | en |
dc.subject | Vascular Endothelial Growth Factor A | en |
dc.subject | von Hippel-Lindau Disease | en |
dc.title | Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. | en |
dc.type | Journal Article | |
plymouth.author-url | https://www.ncbi.nlm.nih.gov/pubmed/15964822 | en |
plymouth.issue | 13 | en |
plymouth.volume | 25 | en |
plymouth.publication-status | Published | en |
plymouth.journal | Mol Cell Biol | en |
dc.identifier.doi | 10.1128/MCB.25.13.5675-5686.2005 | en |
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.place | United States | en |
dc.rights.embargoperiod | Not known | en |
rioxxterms.versionofrecord | 10.1128/MCB.25.13.5675-5686.2005 | en |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | en |
rioxxterms.type | Journal Article/Review | en |