Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2).
Bottom Line: Inhibition of GSK-3 in keratinocytes by retroviral transduction of GSK-binding protein (an endogenous inhibitory protein) or through a highly selective pharmacological inhibitor also resulted in increased keratinocyte proliferation.Both lithium and genetic/pharmacological inhibition of GSK-3 resulted in increased nuclear localization of NFAT2 (NFATc1) and increased NFAT transcriptional activation.Finally, retroviral transduction of NFAT2 increased keratinocyte proliferation whereas siRNA-mediated knockdown of NFAT2 reduced keratinocyte proliferation and decreased epidermal thickness in an organotypic skin equivalent model.
Affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.Show MeSH
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Mentions: Finally, we assessed the effect of knocking down NFAT2 using NFAT siRNA in an epidermal equivalent model and in monolayer cultured human keratinocytes. Knockdown of NFAT2 in primary keratinocytes was confirmed by Western blotting (Jans et al. (manuscript in preparation)). Keratinocytes transfected with NFAT2 siRNA were grown in an epidermal skin equivalent model. Knockdown of NFAT2 resulted in reduced epidermal thickness (Fig. 6A). siRNA-mediated knockdown of NFAT2 reduced keratinocyte growth as assessed by cell counting (Fig. 6B) and SRB assay (data not shown). Together, these data indicate a role of NFAT2 in the regulation of keratinocyte proliferation and cell cycle progression and suggest that lithium induced keratinocyte proliferation may be regulated via GSK-3 and NFAT2.
Affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.