PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity

Two major mechanisms of intracellular protein degradation, autophagy and the ubiquitin-proteasome pathway, operate in mammalian cells. PTEN, which is frequently mutated in glioblastomas, is a tumor suppressor gene that encodes a dual specificity phosphatase that antagonizes the phosphatidylinositol...

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Bibliographic Details
Published in:	PloS one Vol. 8; no. 12; p. e83318
Main Authors:	Errafiy, Rajaa, Aguado, Carmen, Ghislat, Ghita, Esteve, Juan M, Gil, Anabel, Loutfi, Mohammed, Knecht, Erwin
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 13-12-2013 Public Library of Science (PLoS)
Subjects:	1-Phosphatidylinositol 3-kinase AKT protein Apoptosis Autophagy Biodegradation Brain cancer Brain tumors Cancer genetics Cell cycle Cell death Cell Line, Tumor Cells (Biology) Cloning Degradation Development and progression Enzymes Fibroblasts Glioma Glioma - genetics Glioma - metabolism Glioma - pathology Glioma cells Gliomas Humans Intracellular Kinases Lipids Lysosomes - genetics Lysosomes - metabolism Mammalian cells Mutants Phagocytosis Phosphatase Phosphatases Phosphatidate Phosphatase - genetics Phosphatidate Phosphatase - metabolism Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Proteasome Endopeptidase Complex - genetics Proteasome Endopeptidase Complex - metabolism Proteasomes Protein phosphatase Proteins Proteolysis Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism PTEN protein Signal transduction Signaling TOR protein TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Tumor suppressor genes Tumors Ubiquitin Ubiquitin - genetics Ubiquitin - metabolism Ubiquitination Spain
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Summary:	Two major mechanisms of intracellular protein degradation, autophagy and the ubiquitin-proteasome pathway, operate in mammalian cells. PTEN, which is frequently mutated in glioblastomas, is a tumor suppressor gene that encodes a dual specificity phosphatase that antagonizes the phosphatidylinositol 3-kinase class I/AKT/mTOR pathway, which is a key regulator of autophagy. Here, we investigated in U87MG human glioma cells the role of PTEN in the regulation of autophagy and the ubiquitin-proteasome pathway, because both are functionally linked and are relevant in cancer progression. Since U87MG glioma cells lack a functional PTEN, we used stable clones that express, under the control of a tetracycline-inducible system (Tet-on), wild-type PTEN and two of its mutants, G129E-PTEN and C124S-PTEN, which, respectively, lack the lipid phosphatase activity only and both the lipid and the protein phosphatase activities of this protein. Expression of PTEN in U87MG glioma cells decreased proteasome activity and also reduced protein ubiquitination. On the contrary, expression of PTEN increased the autophagic flux and the lysosomal mass. Interestingly, and although PTEN negatively regulates the phosphatidylinositol 3-kinase class I/AKT/mTOR signaling pathway by its lipid phosphatase activity, both effects in U87MG cells were independent of this activity. These results suggest a new mTOR-independent signaling pathway by which PTEN can regulate in opposite directions the main mechanisms of intracellular protein degradation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: RE CA GG JME ML EK. Performed the experiments: RE CA GG AG. Analyzed the data: RE CA GG JME AG EK. Wrote the manuscript: RE CA GG ML EK.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0083318