Essential roles of c-JUN and c-JUN N-terminal kinase (JNK) in neuregulin-increased expression of the acetylcholine receptor epsilon-subunit.
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 epsilon-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 epsilon-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 epsilon-promoter activation. Moreover, overexpression of the JNK dominant-negative mutant inhibited neuregulin-mediated expression of the epsilon-transgene and endogenous epsilon-mRNA. Taken together, our results demonstrate important roles of c-JUN and JNK in neuregulin-mediated expression of the AChR epsilon-subunit gene and suggest that neuregulin activates multiple signaling cascades that converge to regulate AChR epsilon-subunit gene expression.
Si
J
J
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Wang
Q
Q
Mei
L
L
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000235:genetics; D006023:Glycoproteins / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D018482:Muscle, Skeletal / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology; D020880:Neuregulins; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
D006023:Glycoproteins; D046911:Macromolecular Substances; D009414:Nerve Growth Factors; D020880:Neuregulins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; D003609:Dactinomycin; D003513:Cycloheximide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases