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Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):16997-17006. doi: 10.1073/pnas.1900748116. Epub 2019 Aug 2.

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance.

Author information

1
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
2
Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom.
3
Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
4
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
6
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden; susanne.schlisio@ki.se.

Abstract

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.

KEYWORDS:

BIM-EL; VHL; hydroxylation; pheochromocytoma; tumor suppression

PMID:
31375625
PMCID:
PMC6708352
[Available on 2020-02-02]
DOI:
10.1073/pnas.1900748116

Conflict of interest statement

The authors declare no conflict of interest.

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