Hypoxia-inducible factor-2? 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-? (HIF-?). Loss of pVHL causes HIF-? 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-? and B-Myb are targets of pVHL-mediated polyubiquitination and proteasomal degradation. Here, we show that knockdown of HIF-2? 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-2? are both upregulated, and the upregulation of B-Myb requires expression of HIF-2?. We also show that HIF-2? and B-Myb interact in the nucleus, and this interaction is mediated by the central region of HIF-2? and the C-terminal region of B-Myb. These data indicate that oncogenic HIF-2? stabilizes B-Myb to suppress VHL pathogenesis.

SUBMITTER: Okumura F 

PROVIDER: S-EPMC5386292 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature