Inhibition of MuSK expression by CREB interacting with a CRE-like element and MyoD.
The type I receptor-like protein tyrosine kinase MuSK is essential for the neuromuscular junction formation. MuSK expression is tightly regulated during development, but the underlying mechanisms were unclear. Here we identified a novel mechanism by which MuSK expression may be regulated. A cyclic AMP response element (CRE)-like element in the 5'-flanking region of the MuSK gene binds to CREB1 (CRE-binding protein 1). Mutation of this element increases the MuSK promoter activity, suggesting a role for CREB1 in attenuation of MuSK expression. Interestingly, CREB mutants unable to bind to DNA also inhibit MuSK promoter activity, suggesting a CRE-independent inhibitory mechanism. In agreement, CREB1 could inhibit a mutant MuSK transgene reporter whose CRE site was mutated. We provide evidence that CREB interacts directly with MyoD, a myogenic factor essential for MuSK expression in muscle cells. Suppression of CREB expression by small interfering RNA increases MuSK promoter activity. These results demonstrate an important role for CREB1 in the regulation of MuSK expression.
Kim
Chang-Hoon
CH
Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, CB2803, 1120 15th Street, Augusta, Georgia 30912, USA.
Xiong
Wen C
WC
Mei
Lin
L
D024506:5' Flanking Region; D051698:Activating Transcription Factor 2; D000818:Animals; D019556:COS Cells; D050882:CREB-Binding Protein; D002460:Cell Line; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D017930:Genes, Reporter; D051379:Mice; D008822:Mice, Transgenic; D017570:MyoD Protein / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D017570:MyoD Protein; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse