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J. Biol. Chem., Vol. 283, Issue 13, 8736-8745, March 28, 2008

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F1000 Medicine *Must Read* - FREE!

Evidence of Key Role of Cdk2 Overexpression in Pemphigus Vulgaris^*

Alessandro Lanza¹, Nicola Cirillo¹, Raffaele Rossiello^¶, Monica Rienzo^||, Luisa Cutillo^**, Amelia Casamassimi^||, Filomena de Nigris^||, Concetta Schiano^||, Luigi Rossiello, Felice Femiano, Fernando Gombos, and Claudio Napoli^||2

From the Regional Center on Craniofacial Malformations, Clinical Odontostomatology, and ^¶Human Pathology, 1st School of Medicine and Surgery, II University of Naples, 80134 Naples, Italy, the ^||Department of General Pathology, Clinical Pathology and Division of Dermatology, 1st School of Medicine and Surgery, 1st School of Medicine and Surgery, II University of Naples, 80138 Naples, Italy, and the ^**Theleton Institute of Genetics and Medicine of Naples, 80131 Naples, Italy

The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy.

Received for publication, March 13, 2007 , and in revised form, January 8, 2008.

^* This work was supported in part by research funds from Regione Campania to the Centro di Riferimento Regionale per le Cheilognatopalatoschisi (to A. L., N. C., F. F., F. G., and C. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1-S7.

¹ Both authors contributed equally to this study.

² To whom correspondence should be addressed: Dept. of General Pathology, Clinical Pathology, 1st School of Medicine and Surgery, II University of Naples, Complesso S. Andrea delle Dame, Via L. de Crecchio 7, 80138 Naples, Italy. Tel.: 39-081-5667567; Fax: 39-081-450169; E-mail: claudio.napoli{at}unina2.it.

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