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Título: | VHL-P138R and VHL-L163R novel variants: mechanisms of VHL pathogenicity involving HIF-dependent and HIF-independent actions |
Autor: | Mathó, Cecilia Fernández, María Celia Bonanata, Jenner Liu, Xian-De Martin, Ayelen Vieites, Ana Sansó, Gabriela Barontini, Marta Jonasch, Eric Coitiño, Laura E. Pennisi, Patricia Alejandra |
Tipo: | Artículo |
Palabras clave: | VHL, Von Hippel–Lindau, Novel variants, P138R, L163R, Functional characterization, Molecular dynamics, Simulations |
Fecha de publicación: | 2022 |
Resumen: | The von Hippel–Lindau (VHL) disease is an autosomal dominant cancer syndrome caused by mutations in the VHL tumor suppressor gene. VHL protein (pVHL) forms a complex (VBC) with Elongins B-C, Cullin2, and Rbx1. Although other functions have been discovered, the most described function of pVHL is to recognize and target hypoxiainducible factor (HIF) for degradation. This work comprises the functional characterization of two novel variants of the VHL gene (P138R and L163R) that have been described in our center in patients with VHL disease by in vitro, in vivo, and in silico approaches. In vitro, we found that these variants have a significantly shorter half-life compared to wild-type VHL but still form a functional VBC complex. Altered fibronectin deposition was evidenced for both variants using immunofluorescence. In vivo studies revealed that both variants failed to suppress tumor growth. By means of molecular dynamics simulations, we inspected in silico the nature of the changes introduced by each variant in the VBC complex. We have demonstrated the pathogenicity of P138R and L163R novel variants, involving HIFdependent and HIF-independent mechanisms. These results provide the basis for future studies regarding the impact of structural alterations on posttranslational modifications that drive pVHL’s fate and functions. |
Descripción: | Material complementario: https://www.frontiersin.org/articles/10.3389/fendo.2022.854365/full#supplementary-material |
Editorial: | Frontiers Media |
EN: | Frontiers in Endocrinology, 2022, 13: 854365 |
DOI: | 10.3389/fendo.2022.854365 |
ISSN: | 1664-2392 |
Citación: | Mathó, C, Fernández, M, Bonanata, J, y otros. "VHL-P138R and VHL-L163R novel variants: mechanisms of VHL pathogenicity involving HIF-dependent and HIF-independent actions". Frontiers in Endocrinology. [en línea] 2022, 13: 854365. 14 h. DOI: 10.3389/fendo.2022.854365. DOI: 10.3389/fendo.2022.854365 |
Licencia: | Licencia Creative Commons Atribución (CC - By 4.0) |
Aparece en las colecciones: | Publicaciones académicas y científicas - Facultad de Ciencias |
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