title: Protein phosphatase 2A subunit PR70 interacts with pRb and mediates its dephosphorylation.
abstract: The retinoblastoma tumor suppressor protein (pRb) regulates cell proliferation and differentiation via phosphorylation-sensitive interactions with specific targets. While the role of cyclin/cyclin-dependent kinase complexes in the modulation of pRb phosphorylation has been extensively studied, relatively little is known about the molecular mechanisms regulating phosphate removal by phosphatases. Protein phosphatase 2A (PP2A) is constituted by a core dimer bearing catalytic activity and one variable B regulatory subunit conferring target specificity and subcellular localization. We previously demonstrated that PP2A core dimer binds pRb and dephosphorylates pRb upon oxidative stress. In the present study, we identified a specific PP2A-B subunit, PR70, that was associated with pRb both in vitro and in vivo. PR70 overexpression caused pRb dephosphorylation; conversely, PR70 knockdown prevented both pRb dephosphorylation and DNA synthesis inhibition induced by oxidative stress. Moreover, we found that intracellular Ca(2+) mobilization was necessary and sufficient to trigger pRb dephosphorylation and PP2A phosphatase activity of PR70 was Ca(2+) induced. These data underline the importance of PR70-Ca(2+) interaction in the signal transduction mechanisms triggered by redox imbalance and leading to pRb dephosphorylation.
authors.affiliation: Laboratorio Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Magenta
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fasanaro
authors.forename: Sveva
authors.initials: S
authors.lastname: Romani
authors.forename: Valeria
authors.initials: V
authors.lastname: Di Stefano
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: Fabio
authors.initials: F
authors.lastname: Martelli
mesh_terms: D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019281:Dimerization; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016196:S Phase
chemical_list: D021122:Protein Subunits; D016160:Retinoblastoma Protein; D006861:Hydrogen Peroxide; D054648:Protein Phosphatase 2; D002118:Calcium