| First Author | Li S | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 34 | Pages | 16997-17006 |
| PubMed ID | 31375625 | Mgi Jnum | J:278746 |
| Mgi Id | MGI:6358915 | Doi | 10.1073/pnas.1900748116 |
| Citation | Li S, et al. (2019) EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance. Proc Natl Acad Sci U S A 116(34):16997-17006 |
| abstractText | Despite the discovery of the oxygen-sensitive regulation of HIFalpha by the von Hippel-Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFalpha. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFalpha, type 2C mutants encode proteins that preserve their ability to down-regulate HIFalpha. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFalpha or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant. |
