Regulation of the nuclear export of the transcription factor NFATc1 by protein kinases after slow fibre type electrical stimulation of adult mouse skeletal muscle fibres
- 1 March 2007
- journal article
- Published by Wiley in The Journal of Physiology
- Vol. 579 (2), 535-551
- https://doi.org/10.1113/jphysiol.2006.120048
Abstract
The transcription factor nuclear factor of activated T cells (NFAT)c1 has been shown to be involved in turning on slow skeletal muscle fibre gene expression. Previous studies from our laboratory have characterized the stimulation pattern-dependent nuclear import and resting shuttling of NFATc1-green fluorescent protein (GFP) in flexor digitorum brevis (FDB) muscle fibres from adult mouse. In this study, we use viral expression of the transcription factor NFATc1-GFP fusion protein to investigate the mechanisms underlying the nuclear export of the NFATc1-GFP that accumulated in the nuclei of cultured dissociated adult mouse FDB muscle fibres during slow-twitch fibre type electrical stimulation. In these studies, we found that inhibition of either glycogen synthase kinase 3beta (GSK3beta) or casein kinase 1 or 2 (CK1/2) markedly slowed the decay of nuclear NFATc1-GFP after cessation of muscle fibre electrical stimulation, whereas inhibition of casein kinase 1delta, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase and protein kinase A had little effect. Simultaneous inhibition of GSK3beta and CK1/2 completely blocked the nuclear export of NFATc1-GFP after muscle activity. We also developed a simplified model of NFATc1 phosphorylation/dephosphorylation and nuclear fluxes, and used this model to simulate the observed time courses of nuclear NFATc1-GFP with and without NFATc1 kinase inhibition. Our results suggest that GSK3beta and CK1/2 are the major protein kinases that contribute to the removal of NFATc1 that accumulates in muscle fibre nuclei during muscle activity, and that GSK3beta and CK1/2 are responsible for phosphorylating NFATc1 in muscle nuclei in a complementary or synergistic fashion.Keywords
This publication has 42 references indexed in Scilit:
- NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21Nature, 2006
- Control of slow myosin heavy chain 2 gene expression by glycogen synthase kinase activity in skeletal muscle fibersCell and tissue research, 2005
- Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscleThe Journal of cell biology, 2005
- Mitogen‐activated protein kinase signalling pathways in IL‐1β‐dependent rat airway smooth muscle proliferationBritish Journal of Pharmacology, 2004
- Distinct Signaling Pathways Are Activated in Response to Mechanical Stress Applied Axially and Transversely to Skeletal Muscle FibersJournal of Biological Chemistry, 2002
- Glycogen Synthase Kinase-3 Inhibits the DNA Binding Activity of NFATcJournal of Biological Chemistry, 2001
- Identification of Amino Acid Residues and Protein Kinases Involved in the Regulation of NFATc Subcellular LocalizationPublished by Elsevier BV ,2000
- L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neuronsNature, 1999
- TRANSCRIPTION FACTORS OF THE NFAT FAMILY:Regulation and FunctionAnnual Review of Immunology, 1997
- Identification of a Putative Regulator of Early T Cell Activation GenesScience, 1988