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Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.
The Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21(WAF1/Cip1) gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-Jkappa 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.
Alopecia/etiology, Animals, Calcineurin/antagonists &, inhibitors, Calcineurin/metabolism, Cell Cycle Proteins/genetics, Cell Differentiation, Cell Division, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, DNA-Binding Proteins/metabolism, Down-Regulation, Gene Expression Regulation, Developmental, Keratinocytes/cytology, Keratinocytes/metabolism, Mice, Mice, Knockout, NFATC Transcription Factors, Nuclear Proteins/metabolism, Phenotype, Promoter Regions, Genetic, Receptor, Notch1, Receptors, Cell Surface/metabolism, Signal Transduction, Transcription Factors/metabolism
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