Loss of Calcineurin Aα Alters Keratinocyte Survival and Differentiation

Abstract

Calcineurin is a serine/threonine phosphatase that is inhibited by the immunosuppressive drugs cyclosporine and FK506. Although calcineurin has been extensively studied in immune cells, less is known about calcineurin in other systems. There are two primary isoforms of the catalytic subunit of calcineurin, and mice have been created that lack either the alpha isoform (calcineurin A (CnA)alpha(-/-)) or the beta isoform (CnAbeta(-/-)). In this study, we examined the epidermis of CnAalpha(-/-) mice at birth and 4 weeks of age. Histological analyses revealed an attenuation of cells in the stratum spinosum of CnAalpha(-/-) mice. There was no significant difference in proliferation in the epidermis of CnAalpha(-/-) sections, but TUNEL assay revealed increased cell death in the supra-basal layers. Interestingly, the calcineurin substrate nuclear factor of activated T cells (NFATc) was highly expressed in the nucleus of basal epidermal cells in wild-type (WT) mice but was cytoplasmic in CnAalpha(-/-) mice, consistent with a loss of calcineurin activity. Moreover, NFATc activity was decreased in the epidermis of null mice compared with that in WT littermates. Finally, immunohistochemical staining revealed supra-basal expression of keratin 14 and decreased expression of differentiation-associated keratin 10 and involucrin. These findings suggest that calcineurin Aalpha activity is required for the normal differentiation and survival of epidermal cells.

Ethyl acetate fraction of Radix rubiae inhibits cell growth and promotes terminal differentiation in cultured human keratinocytes

“…Calcineurin is the only known serine-threonine phosphatase under calcium-calmodulin control. An increase in the cytoplasmic level of calcium activates calcineurin, which in turn activates the transcription factors (NFATs) and ends up with cell proliferation and differentiation (Pena et al, 2010). Several NFATs, for example, NFAT1, 2, 3 and 5 have been reported to regulate the different stages of keratinocytes differentiation in vitro and in vivo under the influence of calcium (Al-Daraji et al, 2002.…”

Targeting the immune system to treat hypertension

“…Common side-effects of CNIs include renal fibrosis, diabetes, skin cancer and hypertension [23][24][25]. Knockout mouse models of calcineurin indicate that these effects can be directly linked to calcineurin action in the kidney and other organs [26][27][28][29]. Despite the established link between chronic CNI use and hypertension, there is at least one study that tested the effect of tacrolimus (which is associated with less nephrotoxicity than cyclosporine) in an experimental model of hypertension.…”

Regulatory Mechanisms of Calcineurin Phosphatase Activity

“…Our understanding of additional roles of Cn in other cell systems, such as pancreatic -cells [9,10] and skin [11][12][13], is gradually taking shape. Various muscle and neuronal proteins and enzymes are directly dephosphorylated by Cn; however, through the transcription factors NFAT, NF B, and Elk-1 [14][15][16][17][18][19], the realm of Cn extends to the level of regulation of gene expression, as depicted in Fig.…”