Integration of Notch1 and calcineurin/NFAT signaling pathway in keratinocyte growth and differentiation control.
Mammukari, C. Tommasi di Vignano, A. Sharov, A.A. Neilson, J. Havrda, M.C. Roop, D.R. Botchkarev, Vladimir A. Crabtree, G.R. Paolo Dotto, G
Mammukari, C.
Tommasi di Vignano, A.
Sharov, A.A.
Neilson, J.
Havrda, M.C.
Roop, D.R.
Botchkarev, Vladimir A.
Crabtree, G.R.
Paolo Dotto, G
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2005
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Abstract
The Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J¿ protein to the p21 promoter. We show here that Notch 1 activation functions also through a second Calcineurin-dependent mechanism acting on the p21 TATA box-proximal region. Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism. Besides control of the p21 gene, Calcineurin contributes significantly to the transcriptional response of keratinocytes to Notch 1 activation, both in vitro and in vivo. In fact, deletion of the Calcineurin B1 gene in the skin results in a cyclic alopecia phenotype, associated with altered expression of Notch-responsive genes involved in hair follicle structure and/or adhesion to the surrounding mesenchyme. Thus, an important interconnection exists between Notch 1 and Calcineurin-NFAT pathways in keratinocyte growth/differentiation control.
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Mammukari, C., Tommasi di Vignano, A., Sharov, A. A., Neilson, J. and Botchkarev, V.A. et al. (2005). Integration of Notch1 and calcineurin/NFAT signaling pathway in keratinocyte growth and differentiation control. Developmental Cell. Vol. 8, No. 5, pp. 665-676.
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