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J. Biol. Chem., Vol. 280, Issue 6, 4402-4414, February 11, 2005

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S100B Increases Proliferation in PC12 Neuronal Cells and Reduces Their Responsiveness to Nerve Growth Factor via Akt Activation^*

Cataldo Arcuri, Roberta Bianchi, Flora Brozzi, and Rosario Donato

From the Section of Anatomy, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06122 Perugia, Italy

S100B is a Ca²⁺-modulated protein of the EF-hand type expressed in high abundance in a restricted set of cell types including certain neuronal populations. S100B has been suggested to participate in cell cycle progression, and S100B levels are high in tumor cells, compared with normal parental cells. We expressed S100B in the neuronal cell line PC12, which normally does not express the protein, by the Tet-Off technique, and found the following: (i) proliferation was higher in S100B⁺ PC12 cells than in S100B^– PC12 cells; (ii) nerve growth factor (NGF), which decreased the proliferation of S100B^– PC12 cells, was less effective in the case of S100B⁺ PC12 cells; (iii) expression of S100B made PC12 cells resistant to the differentiating effect of NGF; and (iv) interruption of S100B expression did not result in an immediate restoration of PC12 cell sensitivity to the differentiating effect of NGF. Expression of S100B in PC12 cells resulted in activation of Akt; increased levels of p21^WAF1, an inhibitor of cyclin-dependent kinase (cdk) 2 and a positive regulator of cdk4; increased p21^WAF1-cyclin D1 complex formation; and increased phosphorylation of the retinoblastoma suppressor protein, Rb. These S100B-induced effects, as well as the reduced ability of S100B⁺ PC12 cells to respond to NGF, were dependent on Akt activation because they were remarkably reduced or abrogated in the presence of LY294002, an inhibitor of the Akt upstream kinase phosphatidylinositol 3-kinase. Thus, S100B might promote cell proliferation and interfere with NGF-induced PC12 cell differentiation by stimulating a p21^WAF1/cyclin D1/cdk4/Rb/E2F pathway in an Akt-mediated manner.

Received for publication, June 9, 2004 , and in revised form, November 29, 2004.

^* This work was supported by Ministero dell'Istruzione, dell'Università e della Ricerca-University of Perugia (COFIN 1999), Fondo per gli Investimenti della Ricerca di Base (2001), and Fondazione Cassa di Risparmio di Perugia (Project 22202 and Project 2004.0282.020) funds to R. D. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Section of Anatomy, Dept. of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto Casella Postale 81 Succursale 3, 06122 Perugia, Italy. Tel.: 39-075-585-7453/7448; Fax: 39-075-585-7451; E-mail: donato{at}unipg.it.

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