TY - JOUR
T1 - Hypoxia-inducible factor-2α stabilizes the von Hippel-Lindau (VHL) disease suppressor, Mybrelated protein 2
AU - Okumura, Fumihiko
AU - Joo-Okumura, Akiko
AU - Nakatsukasa, Kunio
AU - Kamura, Takumi
N1 - Funding Information:
This work was supported by the Japan society for the promotion of science (JSPS) KAKENHI Grant Numbers 25291023 (to F.O. and T. K.), 25860043 (to F.O.), 24112006 and 15K14474 (to T.K.), 25870312 and 15K18503 (to K.N.), 13J40160 (to A.J.O), and the Uehara Memorial Foundation (to F.O.) and the Inamori Foundation (to F.O.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0175593
DO - 10.1371/journal.pone.0175593
M3 - Article
C2 - 28394947
AN - SCOPUS:85017209579
VL - 12
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 4
M1 - e0175593
ER -