DOI: 10.1091/mbc.9.10.2905. Activation and Cellular Localization of the Cyclosporine A-sensitive Transcription Factor NF-AT in Skeletal Muscle Cells

Activation and Cellular Localization of the Cyclosporine A-sensitive Transcription Factor NF-AT in Skeletal Muscle Cells

10.1091/mbc.9.10.2905

Crossref journal-article

American Society for Cell Biology (ASCB)

Molecular Biology of the Cell (1076)

Abstract

The widely used immunosuppressant cyclosporine A (CSA) blocks nuclear translocation of the transcription factor, NF-AT (nuclear factor of activated T cells), preventing its activity. mRNA for several NF-AT isoforms has been shown to exist in cells outside of the immune system, suggesting a possible mechanism for side effects associated with CSA treatment. In this study, we demonstrate that CSA inhibits biochemical and morphological differentiation of skeletal muscle cells while having a minimal effect on proliferation. Furthermore, in vivo treatment with CSA inhibits muscle regeneration after induced trauma in mice. These results suggest a role for NF-AT–mediated transcription outside of the immune system. In subsequent experiments, we examined the activation and cellular localization of NF-AT in skeletal muscle cells in vitro. Known pharmacological inducers of NF-AT in lymphoid cells also stimulate transcription from an NF-AT–responsive reporter gene in muscle cells. Three isoforms of NF-AT (NF-ATp, c, and 4/x/c3) are present in the cytoplasm of muscle cells at all stages of myogenesis tested. However, each isoform undergoes calcium-induced nuclear translocation from the cytoplasm at specific stages of muscle differentiation, suggesting specificity among NF-AT isoforms in gene regulation. Strikingly, one isoform (NF-ATc) can preferentially translocate to a subset of nuclei within a single multinucleated myotube. These results demonstrate that skeletal muscle cells express functionally active NF-AT proteins and that the nuclear translocation of individual NF-AT isoforms, which is essential for the ability to coordinate gene expression, is influenced markedly by the differentiation state of the muscle cell.

Bibliography

Abbott, K. L., Friday, B. B., Thaloor, D., Murphy, T. J., & Pavlath, G. K. (1998). Activation and Cellular Localization of the Cyclosporine A-sensitive Transcription Factor NF-AT in Skeletal Muscle Cells. Molecular Biology of the Cell, 9(10), 2905â2916.

Authors 5

Karen L. Abbott (first)
Bret B. Friday (additional)
Deepa Thaloor (additional)
T.J. Murphy (additional)
Grace K. Pavlath (additional)

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Dates

Type	When
Created	12 years, 2 months ago (July 2, 2013, 7:12 p.m.)
Deposited	1 year, 3 months ago (May 13, 2024, 1:58 p.m.)
Indexed	1 month, 3 weeks ago (July 8, 2025, 7:07 a.m.)
Issued	26 years, 11 months ago (Oct. 1, 1998)
Published	26 years, 11 months ago (Oct. 1, 1998)
Published Print	26 years, 11 months ago (Oct. 1, 1998)

Funders 0

None

BibTeX

@article{Abbott_1998, title={Activation and Cellular Localization of the Cyclosporine A-sensitive Transcription Factor NF-AT in Skeletal Muscle Cells}, volume={9}, ISSN={1939-4586}, url={http://dx.doi.org/10.1091/mbc.9.10.2905}, DOI={10.1091/mbc.9.10.2905}, number={10}, journal={Molecular Biology of the Cell}, publisher={American Society for Cell Biology (ASCB)}, author={Abbott, Karen L. and Friday, Bret B. and Thaloor, Deepa and Murphy, T.J. and Pavlath, Grace K.}, editor={Yamamoto, Keith R.}, year={1998}, month=oct, pages={2905–2916} }

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  "abstract": "<jats:p>The widely used immunosuppressant cyclosporine A (CSA) blocks nuclear translocation of the transcription factor, NF-AT (nuclear factor of activated T cells), preventing its activity. mRNA for several NF-AT isoforms has been shown to exist in cells outside of the immune system, suggesting a possible mechanism for side effects associated with CSA treatment. In this study, we demonstrate that CSA inhibits biochemical and morphological differentiation of skeletal muscle cells while having a minimal effect on proliferation. Furthermore, in vivo treatment with CSA inhibits muscle regeneration after induced trauma in mice. These results suggest a role for NF-AT\u2013mediated transcription outside of the immune system. In subsequent experiments, we examined the activation and cellular localization of NF-AT in skeletal muscle cells in vitro. Known pharmacological inducers of NF-AT in lymphoid cells also stimulate transcription from an NF-AT\u2013responsive reporter gene in muscle cells. Three isoforms of NF-AT (NF-ATp, c, and 4/x/c3) are present in the cytoplasm of muscle cells at all stages of myogenesis tested. However, each isoform undergoes calcium-induced nuclear translocation from the cytoplasm at specific stages of muscle differentiation, suggesting specificity among NF-AT isoforms in gene regulation. Strikingly, one isoform (NF-ATc) can preferentially translocate to a subset of nuclei within a single multinucleated myotube. These results demonstrate that skeletal muscle cells express functionally active NF-AT proteins and that the nuclear translocation of individual NF-AT isoforms, which is essential for the ability to coordinate gene expression, is influenced markedly by the differentiation state of the muscle cell.</jats:p>",
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