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J. Biol. Chem., Vol. 278, Issue 21, 19509-19517, May 23, 2003

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Oxidative Stress Induces Protein Phosphatase 2A-dependent Dephosphorylation of the Pocket Proteins pRb, p107, and p130^*

Lucia Cicchillitti , Pasquale Fasanaro , Paolo Biglioli ¶, Maurizio C. Capogrossi  and Fabio Martelli  ||

From the Laboratorio di Biologia Vascolare e Terapia Genica, Istituto Cardiologico Fondazione "I. Monzino," Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, Milan, Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Rome, ^¶ Dipartimento di Chirurgia Cardiovascolare, Istituto Cardiologico Fondazione "I. Monzino," IRCCS, Via Parea 4, Milan, Italy

Oxidative stress induces cell death and growth arrest. In this study, the regulation and the functional role of the retinoblastoma family proteins pRb, p107, and p130 in the cellular response to oxidative stress were investigated. Treatment of endothelial cells with H₂O₂ induced rapid hypophosphorylation of the retinoblastoma family proteins. This event did not require p53 or p21^{Waf1/Cip1/Sdi1} and was not associated with cyclin/cyclin-dependent kinase down-modulation. Four lines of evidence indicate that H₂O₂-induced hypophosphorylation of pRb, p107, and p130 was because of the activity of protein phosphatase 2A (PP2A). First, cell treatment with two phosphatase inhibitors, okadaic acid and calyculin A, prevented the hypophosphorylation of the retinoblastoma family proteins, at concentrations that specifically inhibit PP2A. Second, SV40 small t, which binds and inhibits PP2A, when overexpressed prevented H₂O₂-induced dephosphorylation of the retinoblastoma family proteins, whereas a SV40 small t mutant unable to bind PP2A was totally inert. Third, PP2A core enzyme physically interacted with pRb and p107, both in H₂O₂-treated and untreated cells. Fourth, a PP2A phosphatase activity was co-immunoprecipitated with pRb, and the activity of pRb-associated PP2A was positively modulated by cell treatment with H₂O₂. Because DNA damaging agents inhibit DNA synthesis in a pRb-dependent manner, it was determined whether the PP2A-mediated dephosphorylation of the retinoblastoma family proteins played a role in this S-phase response. Indeed, it was found that inhibition of PP2A by SV40 small t over-expression prevented DNA synthesis inhibition induced by H₂O₂.

Received for publication, January 16, 2003 , and in revised form, March 3, 2003.

^|| To whom correspondence should be addressed. Tel.: 39-06-6646-2431/4791; Fax: 39-06-6646-2430; E-mail: f.martelli{at}idi.it.

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