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Molecular Pharmacology

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Research ArticleArticle

Calcineurin Enhances Acetylcholinesterase mRNA Stability during C2-C12 Muscle Cell Differentiation

Z. David Luo, Yibin Wang, Guy Werlen, Shelley Camp, Kenneth R. Chien and Palmer Taylor
Molecular Pharmacology November 1999, 56 (5) 886-894; DOI: https://doi.org/10.1124/mol.56.5.886
Z. David Luo
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Yibin Wang
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Guy Werlen
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Shelley Camp
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Kenneth R. Chien
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Palmer Taylor
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Abstract

Treatment of C2–C12 mouse myoblasts with the immunosuppressant drug cyclosporin A (CsA) enhances the increase in acetylcholinesterase (AChE) expression observed during skeletal muscle differentiation. The enhanced AChE expression is due primarily to increased mRNA stability because CsA treatment increases the half-life of AChE mRNA, but not the apparent transcriptional rate of the gene. Neither tacrolimus (FK506), an immunosuppressive agent with a distinct structure, nor cyclosporine H, an inactive congener of CsA, alters AChE expression. The enhanced AChE expression is associated with the muscle differentiation process, but cannot be triggered by CsA exposure before differentiation. Myoblasts and myotubes of C2–C12 cells express similar amounts of cyclophilin A and FKBP12, immunophilins known to be intracellular-binding targets for CsA and tacrolimus, respectively. However, cellular levels of calcineurin, a calcium/calmodulin-dependent phosphatase known to be the cellular target of ligand-immunophilin complexes, increase 3-fold during myogenesis. Overexpression of constitutively active calcineurin in differentiating cells reduces AChE mRNA levels and CsA antagonizes such an inhibition. Conversely, overexpression of a dominant negative calcineurin construct increases AChE mRNA levels, which are further enhanced by CsA. Thus, a CsA sensitive, calcineurin mediated pathway appears linked to differentiation-induced stabilization of AChE mRNA during myogenesis.

Footnotes

    • Received April 1, 1999.
    • Accepted August 5, 1999.
  • Send reprint requests to: Dr. Palmer Taylor, Department of Pharmacology, Basic Science Bldg./0636, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0636. E-mail:priley{at}ucsd.edu

  • ↵1 Current address: Basel Institute for Immunology, Grenzacherstrasse 487, CH-4005, Basel, Switzerland.

  • This study was supported by National Institutes of Health (Grants GM 18360 to P.T., F32HL09848 to Z.D.L., and HL46345 to K.R.C.) and a grant from the Muscular Dystrophy Association to P.T. G.W. was supported by the Swiss Academy of Medical Sciences and the Swiss National Science Foundation (Grant 823A-046706). The Basel Institute for Immunology was founded and is supported by F. Hoffman-La Roche Ltd., Basel, Switzerland.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Calcineurin Enhances Acetylcholinesterase mRNA Stability during C2-C12 Muscle Cell Differentiation

Z. David Luo, Yibin Wang, Guy Werlen, Shelley Camp, Kenneth R. Chien and Palmer Taylor
Molecular Pharmacology November 1, 1999, 56 (5) 886-894; DOI: https://doi.org/10.1124/mol.56.5.886

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Research ArticleArticle

Calcineurin Enhances Acetylcholinesterase mRNA Stability during C2-C12 Muscle Cell Differentiation

Z. David Luo, Yibin Wang, Guy Werlen, Shelley Camp, Kenneth R. Chien and Palmer Taylor
Molecular Pharmacology November 1, 1999, 56 (5) 886-894; DOI: https://doi.org/10.1124/mol.56.5.886
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