Activation and cellular localization of the cyclosporine A-sensitive transcription factor NF-AT in skeletal muscle cells Article

Abbott, KL, Friday, BB, Thaloor, D et al. (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), 2905-2916. 10.1091/mbc.9.10.2905

cited authors

  • Abbott, KL; Friday, BB; Thaloor, D; Murphy, TJ; Pavlath, GK

authors

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.

publication date

  • January 1, 1998

published in

Digital Object Identifier (DOI)

start page

  • 2905

end page

  • 2916

volume

  • 9

issue

  • 10