Ciclosporin Inhibits Phorbol-Ester-Induced Hyperplastic Transformation and Tumor Promotion in Mouse Skin Probably by Suppression of Ca²⁺/Calmodulin-Dependent Processes such as Phosphorylation of Elongation Factor 2

Abstract

This study deals with the mechanism of the inhibitory effect exerted by the immunosuppressant ciclosporin (CsA) on phorbol-ester-induced inflammation, epidermal hyperplasia and tumor promotion in mouse skin in vivo. This effect coincides with an inhibition of the phosphorylation of a 100-kilodalton protein (p 100) in epidermal cytosol in vitro, which has been identified as elongation factor 2 (EF-2) of protein biosynthesis. Phosphorylation of EF-2 is dependent on Ca²⁺ and calmodulin, and inhibition of EF-2 phosphorylation by CsA is due to an interaction of CsA with calmodulin. The EF-2 phosphorylation system has a metabolic half-life of 1.5 h probably due to a rather rapid turnover rate of the EF-2 kinase. Since CsA inhibits specifically 12–0-tetradecanoylphorbol-13-acetate (TPA)-stimulated but not basal protein synthesis in epidermis, it is proposed that Ca²⁺/calmodulin-dependent phosphorylation of EF-2 is involved in the induction of the hyperplastic response by TPA and that CsA suppresses TPA effects by inhibition of EF-2-phosphorylation and perhaps other calmodulin-dependent processes. The potential applicability of calmodulin inhibitors in the treatment of hyperproliferative skin diseases is discussed.

Osteogenic response to BMP‐2 of hMSCs grown on apatite‐coated scaffolds

“…Calcium elevation or influx increases eEF2 phosphorylation through activation of eEF2 kinase (Marin et al,1997; Iizuka et al,2007; Chen et al,2009). Because the eEF2 phosphorylation system has a rapid turnover rate (Gschwendt et al,1988; Arora et al,2005), the level of p‐eEF2 in a cell is largely controlled by the activity of eEF2 kinase. In chick NM, afferent deprivation leads to a rapid increase in the basal level of intracellular calcium concentration (Zirpel et al,1995a, b; Zirpel and Rubel,1996), which presumably should activate eEF2 kinase and thus enhance eEF2 phosphorylation, which is the opposite of what we observed.…”

Afferent regulation of chicken auditory brainstem neurons: Rapid changes in phosphorylation of elongation factor 2

“…Calcium elevation or influx increases eEF2 phosphorylation through activation of eEF2 kinase (Marin et al, 1997; Iizuka et al, 2007; Chen et al, 2009). Since the eEF2 phosphorylation system has a rapid turnover rate (Gschwendt et al, 1988; Arora et al, 2005), the level of p-eEF2 in a cell is largely controlled by the activity of eEF2 kinase. In chick NM, afferent deprivation leads to a rapid increase in the basal level of intracellular calcium concentration (Zirpel et al, 1995a; b; Zirpel and Rubel, 1996), which presumably should activate eEF2 kinase and thus enhance eEF2 phosphorylation, opposite to what we observed.…”

Effect of Ciclosporin A on Epidermal Keratinocytes in vitro: Lack of a Direct Effect on Calmodulin

“…In kératinocytes the only direct evidence for a CsA-calmodulin interaction is from work by Gschwendt et al [28,29]. They have found that treatment of mouse kératinocytes with CsA in vitro inhibits phorbol esterinduced phosphorylation of elongation fac tor 2.…”