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.
Mammucari
Cristina
C
Department of Biochemistry, Lausanne University, Epalinges, Switzerland.
Tommasi di Vignano
Alice
A
Sharov
Andrey A
AA
Neilson
Joel
J
Havrda
Matthew C
MC
Roop
Dennis R
DR
Botchkarev
Vladimir A
VA
Crabtree
Gerald R
GR
Dotto
G Paolo
GP
D000505:Alopecia / Q000209:etiology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D065095:Calcineurin Inhibitors; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D019703:Calcineurin