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Molecular and Cellular Biology, January 2008, p. 873-882, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00480-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Protein Phosphatase 2A Subunit PR70 Interacts with pRb and Mediates Its Dephosphorylation

Alessandra Magenta,¹ Pasquale Fasanaro,¹ Sveva Romani,¹ Valeria Di Stefano,² Maurizio C. Capogrossi,¹ and Fabio Martelli^1*

Istituto Dermopatico dell'Immacolata-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy,¹ Policlinico San Donato-IRCCS, via Morandi 30, 20097, San Donato Milanese, Milan, Italy²

Received 20 March 2007/ Returned for modification 23 April 2007/ Accepted 27 October 2007

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 Ca²⁺ mobilization was necessary and sufficient to trigger pRb dephosphorylation and PP2A phosphatase activity of PR70 was Ca²⁺ induced. These data underline the importance of PR70-Ca²⁺ interaction in the signal transduction mechanisms triggered by redox imbalance and leading to pRb dephosphorylation.

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* Corresponding author. Mailing address: Laboratorio Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy. Phone: 39-06-6646-2431/4791. Fax: 39-06-6646-2430. E-mail: f.martelli{at}idi.it

Published ahead of print on 8 November 2007.

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Molecular and Cellular Biology, January 2008, p. 873-882, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00480-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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