Cyclin D1, B and A expression and cell turnover in psoriatic skin lesions before and after cyclosporin treatment

Miracco, Clelia; Pellegrino, Michele; Flori, Michael; Vatti, Rosella; Materno, M.; Andreassi, Lucio

doi:10.1046/j.1365-2133.2000.03826.x

Cited by 22 publications

(17 citation statements)

References 42 publications

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“…Although epidermis structure differs significantly between species, we see a strikingly similar phenotype on overexpressing cyclin A/cdk2 in Xenopus embryos. Interestingly, psoriasis in humans is also accompanied by overexpression of cyclin A (Miracco et al, 2000), and our results suggest that this upregulation may help drive the condition. Moreover, a number of cancers, including those derived from skin, show elevated levels of A-type cyclins (Balasubramanian et al, 1998;Kim et al, 2002).…”

Section: Discussionmentioning

confidence: 91%

G1/S phase cyclin-dependent kinase overexpression perturbs early development and delays tissue-specific differentiation inXenopus

et al. 2004

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Overexpression of cyclin A2/cdk2 in post-MBT embryos results in increased proliferation specifically in the epidermis with concomitant disruption of skin architecture and delay in differentiation. Moreover, ectopic cyclin A2/cdk2 also inhibits differentiation of primary neurons but does not affect muscle. Thus, overexpression of a single G1/S phase cyclin/cdk pair disrupts the balance between division and differentiation in the early vertebrate embryo in a tissue-specific manner.

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Section: Discussionmentioning

confidence: 91%

G1/S phase cyclin-dependent kinase overexpression perturbs early development and delays tissue-specific differentiation inXenopus

et al. 2004

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“…Some other authors have also noted a decrease in the Ki-67 index in the course of systemic psoriasis treatment, e.g. with cyclosporine, retinoids, methotrexate or biological drugs [22,27,[33][34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Influence of phototherapy in psoriasis on ki-67 antigen expression: a preliminary study

Jesionek-Kupnicka

Chomiczewska-Skóra²,

Rotsztejn³

2013

pjp

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Antigen Ki-67 is a non-histone nuclear protein, closely connected with cell proliferation. Determining Ki-67 allows for a quick and reliable evaluation of the growth fraction of the studied cell population. It serves as a marker of proliferative activity in neoplasms and other diseases with excessive cell proliferation such as psoriasis. Evaluation of Ki-67 expression in epidermal cells was performed in 10 individuals suffering from plaque psoriasis, before and after one of three methods of phototherapy: broadband UVB, narrowband UVB or PUVA. We observed increased Ki-67 antigen expression in psoriatic lesions. The percentage of Ki-67 positive nuclei in the epidermis affected by the disease ranged from 0 to 30% and in the macroscopically healthy surrounding tissue the percentage was from 0 to 10%. After phototherapy the expression in lesional skin decreased (p < 0.01). The greatest decrease was observed after the application of PUVA therapy (from 25 to 10% of cells, p < 0.05). No significant differences were observed in the perilesional skin with regard to Ki-67 antigen expression before or after phototherapy. On the basis of our own study and studies conducted by other researchers, it can be concluded that reduced Ki-67 expression after the application of PUVA and UVB therapies in the psoriatic epidermis is not a characteristic result of phototherapy only. It is a characteristic property of any effective psoriasis therapy.

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“…A similar effect has been reported for psoriatic skin lesions, where a reduced cell turnover and a reduced expression of cyclin D1 after cyclosporine treatment were shown in vivo. In vitro, FK506 and cyclosporine induced a G 1 phase arrest in growth factor-stimulated cultured human keratinocytes (44,45). The G 1 phase arrest induced by cyclosporine was also observed in the tubular kidney cell line LLC-PK 1 .…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine Inhibits Growth through the Activating Transcription Factor/cAMP-responsive Element-binding Protein Binding Site in the Cyclin D1 Promoter

Schneider¹,

Oswald²,

Wahl

et al. 2002

Journal of Biological Chemistry

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The immunosuppressive agent cyclosporine affects proliferation depending on the cellular system used. In an attempt to study the inhibitory effect of cyclosporine on proliferation of pancreatic acinar cells, we used AR42J cells as a model system. Here we demonstrate that cyclosporine inhibits growth of these cells by inducing G 1 cell cycle arrest. This effect is mediated by the 5 regulatory region of the cyclin D1 gene and leads to a reduction of cyclin D1 mRNA expression and protein abundance. We show that in AR42J cells the proximal cyclin D1 promoter contains a cis-regulated element, which is important for the maintenance of basal transcriptional activity. This element overlaps the described cAMP-responsive element (CRE) and confers cyclosporine sensitivity to the cyclin D1 promoter. Furthermore, the DNA binding activity of the CRE-binding protein (CREB) decreases through cyclosporine treatment and this is mediated by cyclosporine-induced reduction of CREB steady-state levels. These results demonstrate that cyclosporine can inhibit proliferation of acinar cells by targeting the cyclin D1 promoter at the proximal CRE via a reduction of CREB protein abundance.Mammalian cell proliferation is regulated in mid-to late G 1 phase of the cell cycle. The D-type cyclins and the associated cyclin-dependent kinases (CDKs) 1 are thought to be the key regulatory components for progression through G 1 phase and for the commitment of cells to enter S phase. Cyclin D1 and its catalytic partners CDK4 and CDK6 phosphorylate the retinoblastoma tumor suppressor gene product (RB), resulting in the release of E2F transcription factors, which are required for the activation of S phase-specific genes (1, 2). Inhibition of cyclin D1 expression prevents transition of cells from G 1 to S phase, whereas ectopic expression of cyclin D1 shortens the G 1 interval in many cell types, suggesting that cyclin D1 may be ratelimiting for G 1 progression (2, 3). The abundance of cyclin D1 is regulated transcriptionally and through the ubiquitin-proteasome pathway via protein degradation (4). The promoter region of the cyclin D1 gene contains multiple cis-acting elements, including binding sites for activator protein-1 (AP-1), for nuclear factor B (NF-B), for signal transducers and activators of transcription, for SP1, and for activating transcription factor (ATF)/cAMP-responsive element-binding protein (CREB). The ATF/CREB-binding site is implicated in the activation of the cyclin D1 gene by pp60 v-src (5). Furthermore, the estrogeninduced activation of the cyclin D1 promoter depends on the ATF/CREB site in which ATF-2 and c-Jun form heterodimers (6). Moreover, the integrin-linked kinase-dependent induction of the cyclin D1 promoter requires an intact ATF/CREB site, which is important for the maintenance of the basal transcriptional activity, but not for the induction of the cyclin D1 promoter activity in vascular endothelial cells (7,8).The basic leucine zipper transcription factor CREB is ubiquitously expressed and activated by phosphorylatio...

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Cyclin D1, B and A expression and cell turnover in psoriatic skin lesions before and after cyclosporin treatment

Abstract: Overexpression of cyclins B and A, rather than D1 seems to characterize psoriasis. Their evaluation could provide further insights in understanding the development of this disorder and could be used to verify the efficacy of currently used therapies as well as future ones.

Cited by 22 publications

References 42 publications

G1/S phase cyclin-dependent kinase overexpression perturbs early development and delays tissue-specific differentiation inXenopus

G1/S phase cyclin-dependent kinase overexpression perturbs early development and delays tissue-specific differentiation inXenopus

Influence of phototherapy in psoriasis on ki-67 antigen expression: a preliminary study

Cyclosporine Inhibits Growth through the Activating Transcription Factor/cAMP-responsive Element-binding Protein Binding Site in the Cyclin D1 Promoter

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