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The human tumour suppressor PTEN regulates longevity and dauer formation in Caenorhabditis elegans

Oncogene volume 24, pages 20–27 (2005)Cite this article

Abstract

The PTEN tumour suppressor is a phosphatase that dephosphorylates phosphatidylinositol 3, 4, 5 triphosphate (PIP3) and protein substrates. PTEN function is modulated by its carboxy-terminal region, which contains several clustered phosphorylation sites and a PDZ-binding motif (PDZbm). Although PTEN growth suppression effect is well demonstrated, its additional biological roles are less well understood. DAF-18, a Caenorhabditis elegans homologue PTEN, is a component of the insulin/IGF-I signalling pathway that controls entry to the dauer larval stage and adult longevity. To further explore the role of PTEN in the insulin signalling cascade and its possible involvement in the mechanisms of ageing, we undertook a study of PTEN function in C. elegans. We now report that human PTEN can substitute for DAF-18 and restores the dauer and longevity phenotypes in worms devoid of DAF-18. Furthermore, we provide genetic and biochemical evidence that dauer and lifespan control depends on PTEN-mediated regulation of PIP3 levels. Finally, we established that phosphorylation sites in the C-terminus of PTEN and its PDZbm are necessary for PTEN control of the insulin/IGF-I pathway. These results demonstrate that PTEN negatively regulates the insulin/IGF pathway in a whole organism and raise the hypothesis that PTEN may be involved in mammalian ageing.

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Acknowledgements

We are grateful to Drs G Ruvkun and P Hu for kindly providing the mg198 strain. We thank Dr NR Leslie for PTEN 399STOP mutant and Dr Yuji Kohara for cDNA clones. This work was supported by grants from la Ligue Nationale Contre le Cancer (équipe labellisée), Association pour la Recherche contre le Cancer Contract no. 4794 and ARECA-Toulouse. AMC is supported by grants from the NIH (CA95063) and DOD (17-03-1-0682).

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Authors and Affiliations

  1. Laboratoire Génétique et cancer, FRE 2692 CNRS, Université Claude Bernard Lyon 1, Domaine Rockefeller, 8, avenue Rockefeller, 69373 Cedex 08, Lyon, France

    Florence Solari, Angélique Bourbon-Piffaut, Ingrid Masse & Marc Billaud

  2. Inserm U563, Département d'Oncogenèse et signalisation dans les cellules hématopoïétiques, IFR30, Hôpital Purpan, Toulouse, 31059, France

    Bernard Payrastre

  3. The Derald H Ruttenber Cancer Center, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Andrew M -L Chan

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  1. Florence Solari
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Correspondence to Marc Billaud.

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Solari, F., Bourbon-Piffaut, A., Masse, I. et al. The human tumour suppressor PTEN regulates longevity and dauer formation in Caenorhabditis elegans. Oncogene 24, 20–27 (2005). https://doi.org/10.1038/sj.onc.1207978

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