title: PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity.
abstract: 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.
authors.affiliation: Laboratorio de Biología Celular, Centro de Investigación Príncipe Felipe, Valencia, Spain ; Laboratoire de Biochimie et Biologie Moléculaire, Faculté des Sciences, Ain chock, B.P 5366, Casablanca, Morocco.
authors.forename: Rajaa
authors.initials: R
authors.lastname: Errafiy
authors.affiliation: Laboratorio de Biología Celular, Centro de Investigación Príncipe Felipe, Valencia, Spain ; Centro de Investigación Biomédica en Red de Enfermedades, Raras Valencia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Aguado
authors.affiliation: Laboratorio de Biología Celular, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Ghita
authors.initials: G
authors.lastname: Ghislat
authors.affiliation: Laboratorio de Biología Celular, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Esteve
authors.affiliation: Laboratorio de Biología Celular, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: Gil
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, Faculté des Sciences, Ain chock, B.P 5366, Casablanca, Morocco.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Loutfi
authors.affiliation: Laboratorio de Biología Celular, Centro de Investigación Príncipe Felipe, Valencia, Spain ; Centro de Investigación Biomédica en Red de Enfermedades, Raras Valencia, Spain.
authors.forename: Erwin
authors.initials: E
authors.lastname: Knecht
mesh_terms: D001343:Autophagy; D045744:Cell Line, Tumor; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051059:PTEN Phosphohydrolase; D010711:Phosphatidate Phosphatase; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D025801:Ubiquitin; C546842:MTOR protein, human; C112948:lipid phosphate phosphatase; C494929:PTEN protein, human