Essential roles of c-JUN and c-JUN N-terminal kinase (JNK) in neuregulin-increased expression of the acetylcholine receptor ε-subunit

Jutong Si, Qi Wang, Lin Mei

Research output: Contribution to journalArticle

Abstract

Neuregulin is a neural factor implicated in upregulation of acetylcholine receptor (AChR) synthesis at the neuromuscular junction. Previous studies have demonstrated that the extracellular signal-regulated kinase (ERK) subgroup of MAP kinases is required for neuregulin-induced AChR gene expression. We report here that the neuregulin-mediated increase in AChR ε-subunit mRNA was a delayed response in C2C12 muscle cells. Neuregulin induced expression of immediate early genes c-jun and c-fos, which followed and depended on the ERK activation. Treatment of muscle cells with cycloheximide to inhibit c-JUN synthesis at the protein level and suppression of c-JUN function by a dominant-negative mutant blocked neuregulin-induced expression of the ε-subunit gene, indicating an essential role of c-JUN in neuregulin signaling. Furthermore, neuregulin activated c-JUN N-terminal kinase (JNK) in C2C12 muscle cells. Blockade of JNK activation by overexpressing dominant-negative MKK4 inhibited ε-promoter activation. Moreover, overexpression of the JNK dominant-negative mutant inhibited neuregulin-mediated expression of the ε-transgene and endogenous ε-mRNA. Taken together, our results demonstrate important roles of c-JUN and JNK in neuregulin-mediated expression of the AChR ε-subunit gene and suggest that neuregulin activates multiple signaling cascades that converge to regulate AChR ε-subunit gene expression.

Original languageEnglish (US)
Pages (from-to)8498-8508
Number of pages11
JournalJournal of Neuroscience
Volume19
Issue number19
StatePublished - Oct 1 1999

Keywords

  • AChR
  • C-JUN
  • Immediate early gene
  • JNK
  • Neuregulin
  • Neuromuscular junction
  • Synapse

ASJC Scopus subject areas

  • Neuroscience(all)

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