Expression of a constitutively active calcineurin encoded by an intron-retaining mRNA in follicular keratinocytes

Atsushi Fujimura, Hiroyuki Michiue, Tei-ichi Nishiki, Iori Ohmori, Fan Yan Wei, Hideki Matsui, Kazuhito Tomizawa

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Article numbere17685
JournalPLoS One
Volume6
Issue number3
DOIs
Publication statusPublished - 2011

Fingerprint

Calcineurin
keratinocytes
Keratinocytes
Introns
Cyclin G2
introns
Hair
Messenger RNA
hair follicles
hairs
cyclosporine
Hair Follicle
cyclins
Cyclosporine
immunosuppressive agents
Tacrolimus
Immunosuppressive Agents
Growth
Rodentia
rodents

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Expression of a constitutively active calcineurin encoded by an intron-retaining mRNA in follicular keratinocytes. / Fujimura, Atsushi; Michiue, Hiroyuki; Nishiki, Tei-ichi; Ohmori, Iori; Wei, Fan Yan; Matsui, Hideki; Tomizawa, Kazuhito.

In: PLoS One, Vol. 6, No. 3, e17685, 2011.

Research output: Contribution to journalArticle

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