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Cellular and Molecular Biology

Mutation of the proline P81 into a serine modifies the tumour suppressor function of the von Hippel–Lindau gene in the ccRCC

British Journal of Cancer volume 127, pages 1954–1962 (2022)Cite this article

Subjects

Abstract

Background

The von Hippel–Lindau disease is an autosomal dominant syndrome associated with tumour formation in various tissues, such as retina, central nervous system, kidney, and adrenal glands. VHL gene deletion or mutations support the development of various cancers. Unclassified VHL variants also referred as “of unknown significance” result from gene mutations that have an unknown or unclear effect on protein functions. The P81S mutation has been linked to low penetrance Type 1 disease but its pathogenic function was not clearly determined.

Methods

We established a stable cell line expressing the pVHL213 (c.241C>T, P81S) mutant. Using biochemical and physiological approaches, we herein analysed pVHL folding, stability and function in the context of this VHL single missense mutation.

Results

The P81S mutation mostly affects the non-canonical function of the pVHL protein. The cells expressing the pVHL213P81S acquire invasive properties in relation with modified architecture network.

Conclusion

We demonstrated the pathogenic role of this mutation in tumour development in vhl patients and confirm a medical follow up of family carrying the c.241C>T, P81S.

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Fig. 1: Description of the pedigree of the family that is affected by the P81S mutation.
Fig. 2: Representation of the pVHL213 protein structure.
Fig. 3: Characterisation of the stable cell lines expressing the pVHL213-P81S.
Fig. 4: pVHL213-P81S is part of the E3 ligase complex.
Fig. 5: Expression of pVHL213-P81S promotes cell migration.
Fig. 6: Tumourigenic effect of pVHL213-P81S in 786-O cells.

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Data availability

The data that support the findings of this article are available upon request from the corresponding author.

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Acknowledgements

We thank the IGDR for all facilities. We would like to acknowledge S. Dreano (IGDR) for his contribution in plasmid sequencing. We acknowledge the ImPAcCell and MRic microscopy platforms at the SFR BIOSIT (CNRS UMS3480 Rennes). We thank L. Schmitt for his contribution to the experiments perfromed for the revison of the manuscript.

Funding

We thank the LNCC for financial support of this study.

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Authors and Affiliations

  1. CNRS UMR6290, Université Rennes 1, SFR-UMSCNRS 3480-INSERM 018, 2 ave du Pr L Bernard, 35042, Rennes, France

    Franck Chesnel, Emmanuelle Jullion, Olivier Delalande, Anne Couturier, Adrien Alusse, Xavier Le Goff & Yannick Arlot-Bonnemains

  2. Ecole Pratique des Hautes Etudes, EPHE, Université Paris Sciences et Lettres, Paris, France

    Marion Lenglet & Betty Gardie

  3. Nantes Université, CNRS, INSERM, l’Institut du Thorax, F-44000, Nantes, France

    Marion Lenglet & Betty Gardie

  4. Institut de Cancérologie, Boulevard Jacques Monod, 44805, Saint-Herblain, France

    Caroline Abadie

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  1. Franck Chesnel
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Contributions

Conceived and designed the experiments: FC, YA-B. Performed the experiments: FC, AA, AC, EJ, ML, XLG. Analysed the data: FC, XLG, BG, YA-B. Contributed reagents/materials/analysis data from patients: CA, BG. Wrote the paper: YA-B.

Corresponding author

Correspondence to Yannick Arlot-Bonnemains.

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Chesnel, F., Jullion, E., Delalande, O. et al. Mutation of the proline P81 into a serine modifies the tumour suppressor function of the von Hippel–Lindau gene in the ccRCC. Br J Cancer 127, 1954–1962 (2022). https://doi.org/10.1038/s41416-022-01985-2

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