PMID- 15546872
OWN - NLM
STAT- MEDLINE
DCOM- 20050418
LR  - 20220309
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 7
DP  - 2005 Feb 18
TI  - MBNL1 is the primary determinant of focus formation and aberrant insulin receptor 
      splicing in DM1.
PG  - 5773-80
AB  - In myotonic dystrophy 1 (DM1), aggregation of the mutant DMPK RNA into 
      RNA-protein complexes containing MBNL1 and MBNL2 has been linked to aberrant 
      splicing of the insulin receptor (IR) RNA. In a parallel line of investigation, 
      elevated levels of CUG-binding protein (CUG-BP) have been shown to result in 
      altered IR splicing in DM1. The relative importance of MBNL1, MBNL2, and CUG-BP 
      in DM1 pathogenesis is, however, unclear. Here we have demonstrated that either 
      small interfering RNA-mediated down-regulation of MBNL1 and MBNL2 or the 
      overexpression of CUG-BP in normal myoblasts results in abnormal IR splicing. Our 
      results suggest that CUG-BP regulates the equilibrium of splice site selection by 
      antagonizing the facilitatory activity of MBNL1 and MBNL2 on IR exon 11 splicing 
      in a dose-dependent manner. We have shown that CUG-BP levels are elevated in DM1 
      cells by mechanisms that are independent of MBNL1 and MBNL2 loss. Importantly, 
      rescue experiments in DM1 myoblasts demonstrated that loss of MBNL1 function is 
      the key event, whereas the overexpression of CUG-BP plays a secondary role in the 
      aberrant alternative splicing of IR RNA in DM1. Small interfering RNA-mediated 
      down-regulation of MBNL1, MBNL2, and CUG-BP in DM1 myoblasts demonstrated that 
      MBNL1 plays a critical role in the maintenance of DM1 focus integrity. Thus, 
      these experiments demonstrate that sequestration of MBNL1 by the expanded CUG 
      repeats is the primary determinant of both DM1 focus formation and the abnormal 
      splicing of the IR RNA in DM1 myoblasts. The data therefore support 
      MBNL1-mediated therapy for DM1.
FAU - Dansithong, Warunee
AU  - Dansithong W
AD  - Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, 
      Keck School of Medicine, University of Southern California, Los Angeles, CA 
      90033, USA.
FAU - Paul, Sharan
AU  - Paul S
FAU - Comai, Lucio
AU  - Comai L
FAU - Reddy, Sita
AU  - Reddy S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20041116
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (CELF1 Protein)
RN  - 0 (CELF1 protein, human)
RN  - 0 (MBNL1 protein, human)
RN  - 0 (MBNL2 protein, human)
RN  - 0 (RNA-Binding Proteins)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
EIN - J Biol Chem. 2005 May 20;280(20):20176
MH  - Alternative Splicing/*genetics
MH  - CELF1 Protein
MH  - Cell Line
MH  - Down-Regulation
MH  - Exons/genetics
MH  - Humans
MH  - Myoblasts/metabolism
MH  - Myotonic Dystrophy/*genetics/metabolism/*pathology
MH  - RNA-Binding Proteins/genetics/*metabolism
MH  - Receptor, Insulin/*genetics
EDAT- 2004/11/18 09:00
MHDA- 2005/04/19 09:00
CRDT- 2004/11/18 09:00
PHST- 2004/11/18 09:00 [pubmed]
PHST- 2005/04/19 09:00 [medline]
PHST- 2004/11/18 09:00 [entrez]
AID - S0021-9258(19)63081-4 [pii]
AID - 10.1074/jbc.M410781200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Feb 18;280(7):5773-80. doi: 10.1074/jbc.M410781200. Epub 2004 
      Nov 16.