Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation

Mol Cell. 2007 Oct 12;28(1):68-78. doi: 10.1016/j.molcel.2007.07.027.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • CELF1 Protein
  • Cell Line
  • DNA Repeat Expansion
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / physiology
  • Myocardium / cytology
  • Myocardium / metabolism
  • Myotonic Dystrophy / classification
  • Myotonic Dystrophy / genetics
  • Myotonic Dystrophy / metabolism*
  • Myotonin-Protein Kinase
  • Phosphorylation
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Kinase C beta
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Skin / cytology

Substances

  • CELF1 Protein
  • CELF1 protein, human
  • CELF1 protein, mouse
  • DMPK protein, human
  • DMPK protein, mouse
  • Enzyme Inhibitors
  • Isoenzymes
  • RNA, Untranslated
  • RNA-Binding Proteins
  • Myotonin-Protein Kinase
  • Protein-Serine-Threonine Kinases
  • Protein Kinase C
  • Protein Kinase C beta
  • Protein Kinase C-alpha