title: Hypoxia-inducible factor-2α stabilizes the von Hippel-Lindau (VHL) disease suppressor, Myb-related protein 2.
abstract: Ubiquitin ligase von Hippel-Lindau tumor suppressor (pVHL) negatively regulates protein levels of hypoxia-inducible factor-α (HIF-α). Loss of pVHL causes HIF-α accumulation, which contributes to the pathogenesis of von Hippel-Lindau (VHL) disease. In contrast, v-Myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2; B-Myb), a transcription factor, prevents VHL pathogenesis by regulating gene expression of HIF-independent pathways. Both HIF-α and B-Myb are targets of pVHL-mediated polyubiquitination and proteasomal degradation. Here, we show that knockdown of HIF-2α induces downregulation of B-Myb in 786-O cells, which are deficient in pVHL, and this downregulation is prevented by proteasome inhibition. In the presence of pVHL and under hypoxia-like conditions, B-Myb and HIF-2α are both upregulated, and the upregulation of B-Myb requires expression of HIF-2α. We also show that HIF-2α and B-Myb interact in the nucleus, and this interaction is mediated by the central region of HIF-2α and the C-terminal region of B-Myb. These data indicate that oncogenic HIF-2α stabilizes B-Myb to suppress VHL pathogenesis.
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Fumihiko
authors.identifier: http://orcid.org/0000-0002-9995-2110
authors.initials: F
authors.lastname: Okumura
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Joo-Okumura
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nakatsukasa
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kamura
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D061988:Proteasome Inhibitors / Q000494:pharmacology; D000072417:Protein Domains; D055550:Protein Stability; D034741:RNA, Small Interfering; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C064352:MYBL2 protein, human; C497446:VHL protein, human