title: HIF-2alpha enhances beta-catenin/TCF-driven transcription by interacting with beta-catenin.
abstract: The tumor-promoting factors β-catenin and hypoxia-inducible factor (HIF) are often found to be coactivated in rapidly growing tumors. Recently, it was shown that HIF-1α negatively regulates Wnt/β-catenin signaling by sequestering β-catenin from β-catenin/T-cell factor (TCF). However, no investigation has been undertaken on the involvement of HIF-2α in β-catenin regulation. In this study, it was found that, like HIF-1α, HIF-2α interacts with β-catenin, but at a different site. Furthermore, HIF-2α was found to assemble with β-catenin/TCF and facilitate gene transcription. Mutational analyses revealed that transactivation domains of HIF-2α promote p300 coactivator recruitment by β-catenin. Furthermore, HIF-2α and β-catenin were found to associate in the nuclei of 786-0 renal cell carcinoma cells, and HIF-2α was found to be required for β-catenin activation in these cells and for their proliferation. These results suggest that this interaction contributes to the unrestrained growth of tumor cells containing coactivated HIF-2α and β-catenin. Interestingly, these actions of HIF-2α oppose those of HIF-1α on β-catenin and cell growth, and this suggests that HIF-1α/HIF-2α balance may importantly determine cell growth when hypoxia and Wnt stimulation coexist.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Choi
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050881:E1A-Associated p300 Protein; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D000099162:Endothelial PAS Domain-Containing Protein 1; C495270:CTNNB1 protein, human; C532096:TCF4 protein, human; C494360:EP300 protein, human