EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance.
Despite the discovery of the oxygen-sensitive regulation of HIFα 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 HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. 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 HIFα 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.
['Li|Shuijie|S|', 'Rodriguez|Javier|J|', 'Li|Wenyu|W|', 'Bullova|Petra|P|', 'Fell|Stuart M|SM|', 'Surova|Olga|O|', 'Westerlund|Isabelle|I|', 'Topcic|Danijal|D|', 'Bergsland|Maria|M|', 'Stenman|Adam|A|', 'Muhr|Jonas|J|', 'Nistér|Monica|M|', 'Holmberg|Johan|J|', 'Juhlin|C Christofer|CC|', 'Larsson|Catharina|C|', 'von Kriegsheim|Alex|A|', 'Kaelin|William G|WG|', 'Schlisio|Susanne|S|0000-0002-2605-3771']
D000310:Adrenal Gland Neoplasms D000818:Animals D017209:Apoptosis D000072224:Bcl-2-Like Protein 11 D015687:Cell Hypoxia D002945:Cisplatin D019008:Drug Resistance, Neoplasm D006801:Humans D006900:Hydroxylation D064799:Hypoxia-Inducible Factor-Proline Dioxygenases D020935:MAP Kinase Signaling System D051379:Mice D018345:Mice, Knockout D009154:Mutation D016716:PC12 Cells D010673:Pheochromocytoma D059748:Proteolysis D051381:Rats D051794:Von Hippel-Lindau Tumor Suppressor Protein
BIM-EL VHL pheochromocytoma hydroxylation tumor suppression