TY - JOUR
T1 - Ectopic expression of cyclin D3 corrects differentiation of DM1 myoblasts through activation of RNA CUG-binding protein, CUGBP1
AU - Salisbury, Elizabeth
AU - Sakai, Keiko
AU - Schoser, Benedikt
AU - Huichalaf, Claudia
AU - Schneider-Gold, Christiane
AU - Nguyen, Heather
AU - Wang, Gou Li
AU - Albrecht, Jeffrey H.
AU - Timchenko, Lubov T.
N1 - Funding Information:
This work is supported by NIH grants, AR052791, AR49222, and AR44387 (LTT) and by grants from the Deutsche Gesellschaft fur Muskelkranke (BS). BS is member of the German network on muscular dystrophies (MD-NET, 01GM0601) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany). MD-NET is partner of TREAT-NMD.
PY - 2008
Y1 - 2008
N2 - Differentiation of myocytes is impaired in patients with myotonic dystrophy type 1, DM1. CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In this paper, we present evidence that RNA-binding activity of CUGBP1 and its interactions with initiation translation complex eIF2 are differentially regulated during myogenesis by specific phosphorylation and that this regulation is altered in DM1. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA. During differentiation, CUGBP1 is phosphorylated by cyclinD3-cdk4/6 at Ser302, which increases CUGBP1 binding with p21 and C/EBPβ mRNAs. While cyclin D3 and cdk4 are elevated in normal myotubes; DM1 differentiating cells do not increase these proteins. In normal myotubes, CUGBP1 interacts with cyclin D3/cdk4/6 and eIF2; however, interactions of CUGBP1 with eIF2 are reduced in DM1 differentiating cells and correlate with impaired muscle differentiation in DM1. Ectopic expression of cyclin D3 in DM1 cells increases the CUGBP1-eIF2 complex, corrects expression of differentiation markers, myogenin and desmin, and enhances fusion of DM1 myoblasts. Thus, normalization of cyclin D3 might be a therapeutic approach to correct differentiation of skeletal muscle in DM1 patients.
AB - Differentiation of myocytes is impaired in patients with myotonic dystrophy type 1, DM1. CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In this paper, we present evidence that RNA-binding activity of CUGBP1 and its interactions with initiation translation complex eIF2 are differentially regulated during myogenesis by specific phosphorylation and that this regulation is altered in DM1. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA. During differentiation, CUGBP1 is phosphorylated by cyclinD3-cdk4/6 at Ser302, which increases CUGBP1 binding with p21 and C/EBPβ mRNAs. While cyclin D3 and cdk4 are elevated in normal myotubes; DM1 differentiating cells do not increase these proteins. In normal myotubes, CUGBP1 interacts with cyclin D3/cdk4/6 and eIF2; however, interactions of CUGBP1 with eIF2 are reduced in DM1 differentiating cells and correlate with impaired muscle differentiation in DM1. Ectopic expression of cyclin D3 in DM1 cells increases the CUGBP1-eIF2 complex, corrects expression of differentiation markers, myogenin and desmin, and enhances fusion of DM1 myoblasts. Thus, normalization of cyclin D3 might be a therapeutic approach to correct differentiation of skeletal muscle in DM1 patients.
KW - CUG repeats
KW - CUGBP1-eIF2 complex
KW - Cyclin D3
KW - Differentiation
KW - Myotonic dystrophy 1
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U2 - 10.1016/j.yexcr.2008.04.018
DO - 10.1016/j.yexcr.2008.04.018
M3 - Article
C2 - 18570922
AN - SCOPUS:44949120812
SN - 0014-4827
VL - 314
SP - 2266
EP - 2278
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 11-12
ER -