Evidence of key role of Cdk2 overexpression in pemphigus vulgaris.
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.
Lanza
Alessandro
A
Regional Center on Craniofacial Malformations, Clinical Odontostomatology, and Human Pathology, 1st School of Medicine and Surgery, II University of Naples, Naples, Italy.
Cirillo
Nicola
N
Rossiello
Raffaele
R
Rienzo
Monica
M
Cutillo
Luisa
L
Casamassimi
Amelia
A
de Nigris
Filomena
F
Schiano
Concetta
C
Rossiello
Luigi
L
Femiano
Felice
F
Gombos
Fernando
F
Napoli
Claudio
C
D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D010392:Pemphigus / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics
D034741:RNA, Small Interfering; D051357:Cyclin-Dependent Kinase 2