Journal
NUCLEIC ACIDS RESEARCH
Volume 39, Issue 14, Pages 5907-5925Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkr162
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Funding
- Deutsche Forschungsgemeinschaft
- Biotechnology and Biological Sciences Research Council [BB/F018487/1, LKD20458] Funding Source: researchfish
- BBSRC [BB/F018487/1] Funding Source: UKRI
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The nuclear factor of activated T-cells (NFAT) c1 has been shown to be essential for Ca2+-dependent upregulation of myosin heavy chain (MyHC) I/beta expression during skeletal muscle fiber type transformation. Here, we report activation of extracellular signal-regulated kinase (ERK) 1/2 in Ca2+-ionophore-treated C2C12 myotubes and electrostimulated soleus muscle. Activated ERK1/2 enhanced NFATc1-dependent upregulation of a -2.4 kb MyHCI/beta promoter construct without affecting subcellular localization of endogenous NFATc1. Instead, ERK1/2-augmented phosphorylation of transcriptional coactivator p300, promoted its recruitment to NFATc1 and increased NFATc1-DNA binding to a NFAT site of the MyHCI/beta promoter. In line, inhibition of ERK1/2 signaling abolished the effects of p300. Comparison between wild-type p300 and an acetyltransferase-deficient mutant (p300DY) indicated increased NFATc1-DNA binding as a consequence of p300-mediated acetylation of NFATc1. Activation of the MyHCI/beta promoter by p300 depends on two conserved acetylation sites in NFATc1, which affect DNA binding and transcriptional stimulation. NFATc1 acetylation occurred in Ca2+-ionophore treated C2C12 myotubes or electrostimulated soleus. Finally, endogenous MyHCI/beta gene expression in C2C12 myotubes was strongly inhibited by p300DY and a mutant deficient in ERK phosphorylation sites. In conclusion, ERK1/2-mediated phosphorylation of p300 is crucial for enhancing NFATc1 transactivation function by acetylation, which is essential for Ca2+-induced MyHCI/beta expression.
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