Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation.
Details
Serval ID
serval:BIB_B3BA1093BCE3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation.
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424 (Print)
ISSN-L
0027-8424
Publication state
Published
Issued date
2001
Volume
98
Number
17
Pages
9575-9580
Language
english
Abstract
Calcium functions as a trigger for the switch between epithelial cell growth and differentiation. We report here that the calcium/calmodulin-dependent phosphatase calcineurin is involved in this process. Treatment of primary mouse keratinocytes with cyclosporin A, an inhibitor of calcineurin activity, suppresses the expression of terminal differentiation markers and of p21(WAF1/Cip1) and p27(KIP1), two cyclin-dependent kinase inhibitors that are usually induced with differentiation. In parallel with down-modulation of the endogenous genes, suppression of calcineurin function blocks induction of the promoters for the p21(WAF1/Cip1) and loricrin differentiation marker genes, whereas activity of these promoters is enhanced by calcineurin overexpression. The calcineurin- responsive region of the p21 promoter maps to a 78-bp Sp1/Sp3-binding sequence next to the TATA box, and calcineurin induces activity of the p21 promoter through Sp1/Sp3-dependent transcription. We find that the endogenous NFAT-1 and -2 transcription factors, major downstream targets of calcineurin, associate with Sp1 in keratinocytes in a calcineurin-dependent manner, and calcineurin up-regulates Sp1/Sp3-dependent transcription and p21 promoter activity in synergism with NFAT1/2. Thus, our study reveals an important role for calcineurin in control of keratinocyte differentiation and p21 expression, and points to a so-far-unsuspected interconnection among this phosphatase, NFATs, and Sp1/Sp3-dependent transcription.
Keywords
Animals, Binding Sites, Calcineurin/physiology, Cell Differentiation/genetics, Cyclin-Dependent Kinase Inhibitor p21, Cyclins/biosynthesis, Cyclins/genetics, Cyclosporine/pharmacology, DNA-Binding Proteins/physiology, Gene Expression Regulation/drug effects, Genes, Reporter, Green Fluorescent Proteins, Intermediate Filament Proteins/biosynthesis, Intermediate Filament Proteins/genetics, Keratinocytes/cytology, Keratinocytes/metabolism, Luminescent Proteins/genetics, Macromolecular Substances, Membrane Proteins/biosynthesis, Membrane Proteins/genetics, Mice, Mice, Inbred SENCAR, NFATC Transcription Factors, Nuclear Proteins, Promoter Regions, Genetic/drug effects, Protein Subunits, Sp1 Transcription Factor/physiology, Sp3 Transcription Factor, Transcription Factors/physiology, Transcription, Genetic
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 14:58
Last modification date
20/08/2019 15:22