| First Author | Meissner JD | Year | 2011 |
| Journal | Nucleic Acids Res | Volume | 39 |
| Issue | 14 | Pages | 5907-25 |
| PubMed ID | 21498542 | Mgi Jnum | J:182948 |
| Mgi Id | MGI:5317228 | Doi | 10.1093/nar/gkr162 |
| Citation | Meissner JD, et al. (2011) Extracellular signal-regulated kinase 1/2-mediated phosphorylation of p300 enhances myosin heavy chain I/beta gene expression via acetylation of nuclear factor of activated T cells c1. Nucleic Acids Res 39(14):5907-25 |
| abstractText | The nuclear factor of activated T-cells (NFAT) c1 has been shown to be essential for Ca(2+)-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 Ca(2+)-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 Ca(2+)-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 Ca(2+)-induced MyHCI/beta expression. |
