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: Primary keratinocytes were treated with lithium (10 mM) for 48 h and NFAT2 localization was assessed by immunostaining. Increased nuclear localization of NFAT2 was seen following lithium treatment (Fig. 4A). Western blotting of lysates from primary human keratinocytes treated with lithium (10 mM) showed an increase in expression of NFAT2 isoforms at 48 h (Fig. 4B). Significantly increased transcriptional activation by therapeutically relevant concentrations of lithium (2 mM) was shown between 24 and 168 h, two-way ANOVA P = 0.039 (Fig. 4C). Thus, 2 mM lithium induced prolonged NFAT transcriptional activation in keratinocytes up to 7 days and at time points where we observed lithium-induced keratinocyte proliferation (Fig. 1).
Affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.