VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions
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 r...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.854365/full |
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| author | Cecilia Mathó María Celia Fernández Jenner Bonanata Xian-De Liu Ayelen Martin Ana Vieites Gabriela Sansó Marta Barontini Eric Jonasch E. Laura Coitiño Patricia Alejandra Pennisi |
| author_facet | Cecilia Mathó María Celia Fernández Jenner Bonanata Xian-De Liu Ayelen Martin Ana Vieites Gabriela Sansó Marta Barontini Eric Jonasch E. Laura Coitiño Patricia Alejandra Pennisi |
| author_sort | Cecilia Mathó |
| collection | DOAJ |
| description | 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 hypoxia-inducible 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 HIF-dependent 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. |
| first_indexed | 2024-12-13T19:57:57Z |
| format | Article |
| id | doaj.art-0530ee22a66f41148a78696477d8fad4 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-13T19:57:57Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-0530ee22a66f41148a78696477d8fad42022-12-21T23:33:16ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-03-011310.3389/fendo.2022.854365854365VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent ActionsCecilia Mathó0María Celia Fernández1Jenner Bonanata2Xian-De Liu3Ayelen Martin4Ana Vieites5Gabriela Sansó6Marta Barontini7Eric Jonasch8E. Laura Coitiño9Patricia Alejandra Pennisi10Centro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas- Fundación de Endocrinología Infantil (CONICET-FEI) División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, ArgentinaCentro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas- Fundación de Endocrinología Infantil (CONICET-FEI) División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, ArgentinaLaboratorio de Química Teórica y Computacional (LQTC), Instituto de Química Biológica, Facultad de Ciencias and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, UruguayUniversity of Texas MD Anderson Cancer Center, Houston, TX, United StatesCentro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas- Fundación de Endocrinología Infantil (CONICET-FEI) División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, ArgentinaCentro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas- Fundación de Endocrinología Infantil (CONICET-FEI) División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, ArgentinaCentro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas- Fundación de Endocrinología Infantil (CONICET-FEI) División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, ArgentinaCentro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas- Fundación de Endocrinología Infantil (CONICET-FEI) División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, ArgentinaUniversity of Texas MD Anderson Cancer Center, Houston, TX, United StatesLaboratorio de Química Teórica y Computacional (LQTC), Instituto de Química Biológica, Facultad de Ciencias and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, UruguayCentro de Investigaciones Endocrinológicas Dr. César Bergadá (CEDIE), Consejo Nacional de Investigaciones Científicas y Técnicas- Fundación de Endocrinología Infantil (CONICET-FEI) División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, ArgentinaThe 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 hypoxia-inducible 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 HIF-dependent 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.https://www.frontiersin.org/articles/10.3389/fendo.2022.854365/fullVHLvon Hippel–Lindaunovel variantsP138RL163Rfunctional characterization |
| spellingShingle | Cecilia Mathó María Celia Fernández Jenner Bonanata Xian-De Liu Ayelen Martin Ana Vieites Gabriela Sansó Marta Barontini Eric Jonasch E. Laura Coitiño Patricia Alejandra Pennisi VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions Frontiers in Endocrinology VHL von Hippel–Lindau novel variants P138R L163R functional characterization |
| title | VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions |
| title_full | VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions |
| title_fullStr | VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions |
| title_full_unstemmed | VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions |
| title_short | VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions |
| title_sort | vhl p138r and vhl l163r novel variants mechanisms of vhl pathogenicity involving hif dependent and hif independent actions |
| topic | VHL von Hippel–Lindau novel variants P138R L163R functional characterization |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.854365/full |
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