Abstract
The von Hippel–Lindau (VHL) syndrome is a rare inherited cancer, caused by mutations in the VHL gene, many of which render the VHL protein (pVHL) unstable. pVHL is a tumor-suppressor protein implicated in a variety of cellular processes, most notably in response to changes in oxygen availability, due to its role as part of an E3-ligase complex which targets the hypoxia-inducible factor (HIF) for degradation. Previously we reported, using in silico and in vitro analyses, that common oncogenic VHL mutations render pVHL less stable than the wild-type protein, distort its core domain and as a result reduce the ability of the protein to bind its target HIF-1α. Among various chemical chaperones tested, arginine was the most effective in refolding mutant of pVHL. Here we examined the consequences of administering L- or D-arginine to a Drosophila VHL model and to human renal carcinoma cells, both expressing misfolded versions of human pVHL. Arginine treatment increased pVHL solubility in both models and increased the half-life of the mutant pVHL proteins in the cell culture. In both models, L- as well as D-arginine enhanced the ability of wild-type pVHL and certain misfolded mutant versions of pVHL to bind ODD, the HIF-derived target peptide, reflecting restoration of pVHL function. Moreover, continuous feeding of Drosophila expressing misfolded versions of pVHL either L- or D-arginine rich diet rescued their lethal phenotype. Collectively, these in vivo results suggest that arginine supplementation should be examined as a potential novel treatment for VHL cancer syndrome.
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Acknowledgements
We are grateful to Sivan Peled and the Segal-Gazit research groups for fruitful discussions. This work was supported in part by the Israel Cancer Association, the Cancer Biology Research Center in Tel Aviv University, and the VHL Alliance (to DS).
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This work was supported in part by the Israel Cancer Association, the Cancer Biology Research Center in Tel Aviv University, and the VHL Alliance (to DS).
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Shmueli, M.D., Levy-Kanfo, L., Haj, E. et al. Arginine refolds, stabilizes, and restores function of mutant pVHL proteins in animal model of the VHL cancer syndrome. Oncogene 38, 1038–1049 (2019). https://doi.org/10.1038/s41388-018-0491-x
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DOI: https://doi.org/10.1038/s41388-018-0491-x