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.

Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) expression in glioblastoma is driven by ETS1- and MYBL2-dependent transcriptional activation

“…Indeed, ETS1 is known to regulate the VEGF promoter and its transcription [ 59 ], and ETS1 expression is associated with a higher density of microvessels in tumors [ 60 ]. MYBL2 expression was reported to be induced under ischemic conditions in rat brains [ 61 ], stabilized by HIF-2α [ 62 ], and to protect cells toward hypoxia-induced apoptosis [ 63 ]. Additionally, 4EBP1 has been shown to promote the selective translation of VEGF or HIF-1A mRNAs in response to hypoxia [ 7 ].…”

Coordinating gene expression during the cell cycle

“…This is of particular importance since elevated expression of B-MYB is sufficient to disrupt the DREAM complex [81], and the presence of FOXM1 in G1 promotes entry into S phase [93]. FOXM1 is degraded by the APC/C:FZR1 complex in G1 [93,94], while B-MYB is degraded in confluent cells by pVHL: CUL2 complexes [95] (Figure 4, confluent G0/G1). Receptor tyrosine kinase-dependent phosphorylation of B-MYB at Y15 blocked degradation by pVHL:CUL2 [95], further linking these degradation events with proliferative signaling.…”

“…FOXM1 is degraded by the APC/C:FZR1 complex in G1 [93,94], while B-MYB is degraded in confluent cells by pVHL: CUL2 complexes [95] (Figure 4, confluent G0/G1). Receptor tyrosine kinase-dependent phosphorylation of B-MYB at Y15 blocked degradation by pVHL:CUL2 [95], further linking these degradation events with proliferative signaling.…”

Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs

“…von Hippel-Lindau tumor suppressor (pVHL) negatively regulates protein levels of hypoxiainducible factor-α (HIF-α), which provides fuel to the tumor cell. Thus, loss of pVHL leads to HIF-α accumulation, which contributes to the pathogenesis of von Hippel-Lindau (VHL) disease (Okumura et al 2017;Deeks 2021;Hasanov 2021).…”