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

Kuyumcu-Martinez, N. Muge; Wang, Guey-Shin; Cooper, Thomas A.

doi:10.1016/j.molcel.2007.07.027

Cited by 396 publications

(432 citation statements)

References 36 publications

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“…15 In addition, in DM1 cells, another splicing trans-factor CUG-binding protein encoded by CUGBP1 is hyperphosphorylated by protein kinase C and is stabilized. [16][17][18] Dysregulation of the two splicing trans-factors then causes aberrant splicing of their target genes. A total of 28 exons/introns of 22 genes have been identified to date in the skeletal and cardiac muscles in myotonic dystrophy (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

et al. 2012

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Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder in which abnormally expanded CTG repeats of DMPK sequestrate a splicing trans-factor MBNL1 and upregulate another splicing trans-factor CUGBP1. To identify a diverse array of aberrantly spliced genes, we performed the exon array analysis of DM1 muscles. We analyzed 72 exons by RT-PCR and found that 27 were aberrantly spliced, whereas 45 were not. Among these, 25 were novel and especially splicing aberrations of LDB3 exon 4 and TTN exon 45 were unique to DM1. Retrospective analysis revealed that four parameters efficiently detect aberrantly spliced exons: (i) the signal intensity is high; (ii) the ratio of probe sets with reliable signal intensities (that is, detection above background P-value ¼ 0.000) is high within a gene; (iii) the splice index (SI) is high; and (iv) SI is deviated from SIs of the other exons that can be estimated by calculating the deviation value (DV). Application of the four parameters gave rise to a sensitivity of 77.8% and a specificity of 95.6% in our data set. We propose that calculation of DV, which is unique to our analysis, is of particular importance in analyzing the exon array data. INTRODUCTIONAlternative splicing regulates developmental stage-specific and tissuespecific gene expressions and markedly expands the proteome diversity with a limited number of genes. High-throughput sequencing of total mRNAs expressed in cells has revealed that 98% or more of multiexon genes are alternatively spliced, 1 with an average of seven alternative splicing per multiexon gene. 2 Alternative splicing is achieved by exonic/intronic splicing enhancers/silencers (ESE, ISE, ESS, ISS) in combination with spatial and temporal expression of trans-acting splicing factors, such as serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins. 3,4 Aberrations of alternative splicing are mediated by either mutations disrupting splicing cis-elements or dysregulation of splicing trans-factors. 5,6 Myotonic dystrophy is an autosomal dominant multisystem disorder affecting the skeletal muscles, eye, heart, endocrine system and central nervous system. The clinical symptoms include muscle weakness and wasting, myotonia, cataract, insulin resistance, hypogonadism, cardiac conduction defects, frontal balding and intellectual

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Section: Introductionmentioning

confidence: 99%

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

et al. 2012

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“…12 Cell models are also available, such as C 2 C 12 lines expressing the (CTG) n expansion [13][14][15][16][17] or human DM1 fibroblasts converted into myoblasts by the induction of the myogenic factor MyoD. 18,19 Use of human DM1 primary Received 06.8.09; revised 18.12.09; accepted 15.1.10; Edited by RA Knight; published online 30.4.10 …”

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“…12 Cell models are also available, such as C 2 C 12 lines expressing the (CTG) n expansion [13][14][15][16][17] or human DM1 fibroblasts converted into myoblasts by the induction of the myogenic factor MyoD. 18,19 Use of human DM1 primary myoblasts cultures has been rare, owing to limited availability, and has resulted in contradictory findings. [20][21][22][23][24][25][26][27][28][29][30][31] Various experimental models have been used to speculate about the possible effects of the DM1 mutation on the myogenic process and thus find explanation for the severe skeletal muscle immaturity and wasting of DM muscle.…”

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confidence: 99%

“…16 The most commonly accepted theory is that (CTG) n expansion could affect differentiation of DM myoblasts by interfering with the signals leading to the withdrawal of cell cycle and the shift toward the differentiation program. 26,32,33 However, it should be noted that the majority of the data on in vitro differentiation of DM muscle cells derive from studies on DM1 fibroblasts converted into skeletal muscle, 18,19 from primary muscle cell cultures obtained from cDM1 fetuses 31 or from mouse muscle cells. 14,15,17,33,34 No studies focusing on muscle differentiation of human primary DM1 myoblasts cultures obtained from adult muscle DM1 biopsies are available, underlining the need to work with a model as close as possible to human regenerating skeletal muscle.…”

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Normal myogenesis and increased apoptosis in myotonic dystrophy type-1 muscle cells

et al. 2010

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Myotonic dystrophy (DM) is caused by a (CTG) n expansion in the 3 0 -untranslated region of DMPK gene. Mutant transcripts are retained in nuclear RNA foci, which sequester RNA binding proteins thereby misregulating the alternative splicing. Controversy still surrounds the pathogenesis of the DM1 muscle distress, characterized by myotonia, weakness and wasting with distal muscle atrophy. Eight primary human cell lines from adult-onset (DM1) and congenital (cDM1) patients, (CTG) n range 90-1800, were successfully differentiated into aneural-immature and contracting-innervated-mature myotubes. Morphological, immunohistochemical, RT-PCR and western blotting analyses of several markers of myogenesis indicated that in vitro differentiation-maturation of DM1 myotubes was comparable to age-matched controls. In all pathological muscle cells, (CTG) n expansions were confirmed by long PCR and RNA fluorescence in situ hybridization. Moreover, the DM1 myotubes showed the splicing alteration of insulin receptor and muscleblind-like 1 (MBNL1) genes associated with the DM1 phenotype. Considerable myotube loss and atrophy of 15-day-differentiated DM1 myotubes indicated activated catabolic pathways, as confirmed by the presence of apoptotic (caspase-3 activation, cytochrome c release, chromatin fragmentation) and autophagic (P62/LC3) markers. Z-VAD treatment significantly reduced the decrease in myonuclei number and in average width in 15-day-differentiated DM1 myotubes. We thus propose that the muscle wasting typical in DM1 is due to impairment of muscle mass maintenanceregeneration, through premature apoptotic-autophagic activation, rather than altered myogenesis. Myotonic dystrophy (DM) is a multi-systemic disorder caused by two different microsatellite expansions in non-coding regions. Together, these two mutations affect 1 out of 8000 individuals and represent the most common form of muscular dystrophy in adults. DM1 and DM2 have common symptoms such as myotonia, muscle weakness and early cataract development. 1,2 Although DM1 and DM2 initially affect different muscles (distal versus proximal), histological analysis of the muscular tissues shows common aspects such as central nucleation. The classic form of DM1 is characterized by muscle distress with myotonia, progressive muscle weakness and wasting. Atrophy has also been reported, occurring preferentially in type-1 fibers in DM1 and in type-2 in DM2. 3 DM1 but not DM2 also presents a congenital form (cDM1), characterized by a high neonatal mortality and symptoms such as hypotonia, mental retardation and respiratory distress. 4,5 DM1 is associated with an unstable (CTG) n trinucleotide expansion located in the 3 0 -untranslated (3 0 -UTR) region of the DM protein kinase (DMPK) gene on chromosome 19q13.3. The mutant DMPK transcript, containing the expanded (CTG) n sequence, accumulates in discrete nuclear foci able to sequester various nuclear factors such as RNAbinding proteins or splicing regulators, causing different and highly variable downstream deleterious effects. 2,6...

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“…and demonstrated reversal of muscle degeneration (de Haro et al, 2006). CUGBP1 was shown to be up-regulated in DM1 due to PKC activation and subsequent CUGBP1 protein hyperphosphorylation and stabilization (Kuyumcu-Martinez et al, 2007). Pharmacological blocking of PKC activity in a heart-specific DM1 mouse model ameliorated several DM1 symptoms.…”

Section: Rna-binding Proteinsmentioning

confidence: 98%

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

Mastroyiannopoulos

Shammas

Phylactou

2010

Biology of the Cell

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Cyprus DM1 (myotonic dystrophy type I) is a common form of muscular dystrophy that affects mainly adults. It is a disease that belongs to the group of defective RNA export diseases, since a major part of the pathogenic mechanism of the disease is the retention of the mutant transcripts in the cell nucleus. The presence of an expanded CUG trinucleotide repeat in the 3 -UTR (3 -untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene causes the attraction of RNA-binding proteins by the nuclear-located mutant transcripts. As a result of the occupation of the RNA-binding proteins, there is defective mis-splicing of several cellular transcripts. This is believed to be a major pathogenic mechanism of the disease and any attempt to repair the activities of the RNA-binding proteins or target the mutant transcripts should be beneficial for the patients. Certain approaches have been described in the literature and they demonstrate progress in various directions. The purpose of the present review is to summarize the successful attempts to tackle the pathogenesis caused by nuclear retention of mutant transcripts in myotonic dystrophy and to discuss the possible gains from such approaches.

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

Cited by 396 publications

References 36 publications

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

Normal myogenesis and increased apoptosis in myotonic dystrophy type-1 muscle cells

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

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