ACTIVATION AND CELLULAR-LOCALIZATION OF THE CYCLOSPORINE A-SENSITIVE TRANSCRIPTION FACTOR NF-AT IN SKELETAL-MUSCLE CELLS

Citation
Kl. Abbott et al., ACTIVATION AND CELLULAR-LOCALIZATION OF THE CYCLOSPORINE A-SENSITIVE TRANSCRIPTION FACTOR NF-AT IN SKELETAL-MUSCLE CELLS, Molecular biology of the cell, 9(10), 1998, pp. 2905-2916
Citations number
42
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell Biology",Biology
Journal title
ISSN journal
1059-1524
Volume
9
Issue
10
Year of publication
1998
Pages
2905 - 2916
Database
ISI
SICI code
1059-1524(1998)9:10<2905:AACOTC>2.0.ZU;2-1
Abstract
The widely used immunosuppressant cyclosporine A (CSA) blocks nuclear translocation of the transcription factor, NF-AT (nuclear factor of ac tivated T cells), preventing its activity, mRNA for several NF-AT isof orms has been shown to exist in cells outside of the immune system, su ggesting a possible mechanism for side effects associated with CSA tre atment. In this study, we demonstrate that CSA inhibits biochemical an d 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 stimula te transcription from an NF-AT-responsive reporter gene in muscle cell s. 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 sp ecificity among NF-AT isoforms in gene regulation. Strikingly, one iso form (NF-ATc) can preferentially translocate to a subset of nuclei wit hin a single multinucleated myotube. These results demonstrate that sk eletal muscle cells express functionally active NF-AT proteins and tha t the nuclear translocation of individual NF-AT isoforms, which is ess ential for the ability to coordinate gene expression, is influenced ma rkedly by the differentiation state of the muscle cell.