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: NFAT signaling regulates proliferation in a number of cellular systems as previously indicated. We hypothesized that inhibition of GSK-3 by lithium leading to increased NFAT activity could result in increased proliferation of keratinocytes and that this may be relevant to the actions of lithium in provoking psoriasis. Overexpression of pLEGFP-GSKBP induced increased nuclear NFAT2 (Fig. 3C). To investigate the role of NFAT2 in regulating keratinocyte proliferation, we synchronized HaCaTs in G1 by serum starvation and then transduced cells with pLEGFP-NFAT2. A time-dependent increase in proliferation was seen up to 120 h (Fig. 5A, P < 0.001) following transduction with pLEGFP-NFAT2 compared to empty vector. In addition, transduction with pLEGFP-NFAT2 resulted in an increase in the proportion of cells in S phase compared to empty vector at 24 h (Fig. 5B). Also, following retroviral transduction of K14 keratinocytes with pLEGFP-NFAT2, increased proliferation was seen at 7 days (P = 0.01) compared to empty vector (data not shown).
Affiliation: Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.