Expression of a Constitutively Active Calcineurin Encoded by an Intron-Retaining mRNA in Follicular Keratinocytes
Open Access
- 14 March 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (3), e17685
- https://doi.org/10.1371/journal.pone.0017685
Abstract
Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA) and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn). The calcineurin (Cn)/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca2+ and dephosphorylated NFATc2 under low Ca2+ levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development.Keywords
This publication has 42 references indexed in Scilit:
- Alternative splicing: A missing piece in the puzzle of intron gainProceedings of the National Academy of Sciences of the United States of America, 2008
- Cytoplasmic BK Ca channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neuronsProceedings of the National Academy of Sciences of the United States of America, 2008
- NFATc1 Balances Quiescence and Proliferation of Skin Stem CellsCell, 2008
- A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regenerationThe Journal of cell biology, 2007
- Role of purine-rich exonic splicing enhancers in nuclear retention of pre-mRNAsProceedings of the National Academy of Sciences of the United States of America, 2007
- Scratching the surface of skin developmentNature, 2007
- Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrestExperimental Cell Research, 2006
- NFAT SignalingCell, 2002
- A Comprehensive Guide for the Accurate Classification of Murine Hair Follicles in Distinct Hair Cycle StagesJournal of Investigative Dermatology, 2001
- A dual role for BBP/ScSF1 in nuclear pre-mRNA retention and splicingThe EMBO Journal, 2000