期刊
MOLECULAR CELL
卷 28, 期 1, 页码 68-78出版社
CELL PRESS
DOI: 10.1016/j.molcel.2007.07.027
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资金
- NHLBI NIH HHS [R01 HL045565-17, R01HL45565, R01 HL045565] Funding Source: Medline
- NIAMS NIH HHS [1F32AR052630-01, F32 AR052630, R01 AR045653, R01AR45653, R01 AR045653-09] Funding Source: Medline
The genetic basis of myotonic dystrophy type 1 (DM1) is a CTG expansion in the 3'untranslated region (UTR) of DMPK. The pathogenic mechanism involves an RNA gain of function in which the repeat-containing transcripts accumulate in nuclei and alter the functions of RNA-binding proteins such as CUG-binding protein 1 (CUGBP1). CUGBPI levels are increased in DM1 myoblasts, heart, and skeletal muscle tissues and in some DM1 mouse models. However, the molecular mechanisms for increased CUGBP1 in DM1 are unclear. Here, we demonstrate that expression of DMPK-CUG-repeat RNA results in hyperphosphorylation and stabilization of CUGBP1. CUGBP1 is hyperphosphorylated in DM1 tissues, cells, and a DM1 mouse model. Activation of PKC is required for CUGBP1 hyperphosphorylation in DM1 cells, and PKC alpha and Oil directly phosphorylate CUGBP1 in vitro. These results indicate that inappropriate activation of the PKC pathway contributes to the pathogenic effects of a noncoding RNA.
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