Increased Steady-State Levels of CUGBP1 in Myotonic Dystrophy 1 Are Due to PKC-Mediated Hyperphosphorylation

Neslihan Martinez, Guey Shin Wang, Thomas A. Cooper

Research output: Contribution to journalArticle

263 Citations (Scopus)

Abstract

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). CUGBP1 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 PKCα and βII directly phosphorylate CUGBP1 in vitro. These results indicate that inappropriate activation of the PKC pathway contributes to the pathogenic effects of a noncoding RNA.

Original languageEnglish (US)
Pages (from-to)68-78
Number of pages11
JournalMolecular Cell
Volume28
Issue number1
DOIs
StatePublished - Oct 12 2007
Externally publishedYes

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Myotonic Dystrophy
Carrier Proteins
RNA
Untranslated RNA
Myoblasts
3' Untranslated Regions
Myocardium
Skeletal Muscle
Muscles

Keywords

  • HUMDISEASE
  • RNA

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Increased Steady-State Levels of CUGBP1 in Myotonic Dystrophy 1 Are Due to PKC-Mediated Hyperphosphorylation. / Martinez, Neslihan; Wang, Guey Shin; Cooper, Thomas A.

In: Molecular Cell, Vol. 28, No. 1, 12.10.2007, p. 68-78.

Research output: Contribution to journalArticle

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abstract = "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). CUGBP1 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 PKCα and βII 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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