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Integration of Notch1 and calcineurin/NFAT signaling pathway in keratinocyte growth and differentiation control.

By C. Mammukari, A. Tommasi di Vignano, A.A. Sharov, J. Neilson, M.C. Havrda, D.R. Roop, Vladimir A. Botchkarev, G.R. Crabtree and G Paolo Dotto

Abstract

NoThe 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

Topics: Development, Regulation(control), Differentiation, Growth, Keratinocyte, Signal transduction, Calcineurin
Year: 2005
DOI identifier: 10.1016/j.devcel.2005.02.016
OAI identifier: oai:bradscholars.brad.ac.uk:10454/3660
Provided by: Bradford Scholars
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