Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myotonic dystrophy is a dominantly inherited disorder with multisystemic clinical features affecting skeletal muscle, the heart, the eye, the endocrine system. Two genetic loci have been identified. The mutation responsible for DM1 was identified as a CTG expansion located in 3' untranslated region of the myotonia dystrophica protein kinase gene (DMPK). The molecular pathogenesis of DM1 has been controversial. Myotonic dystrophy type 2 (DM2) which is caused by an untranslated CCTG expansion of zinc finger protein 9 (ZNF9), has been recently discovered. The clinical features common to both diseases are caused by a gain of function RNA mechanism in which the CUG and CCUG repeats alter cellular function. The long PCR based method is useful for the molecular diagnosis for these diseases.
...
PMID:[Myotonic dystrophy]. 1577 41

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder associated with a (CUG)n expansion in the 3'-untranslated region of the DMPK (DM1 protein kinase) gene. Mutant DMPK mRNAs containing the trinucleotide expansion are retained in the nucleus of DM1 cells and form discrete foci. The nuclear sequestration of RNA binding proteins and associated factors binding to the CUG expansions is believed to be responsible for several of the splicing defects observed in DM1 patients and could ultimately be linked to DM1 muscular pathogenesis. Several RNA binding proteins capable of co-localizing with the nuclear-retained mutant DMPK mRNAs have already been identified but none can account for the nuclear retention of the mutant transcripts. Here, we have employed a modified UV crosslinking assay to isolate proteins bound to mutant DMPK-derived RNA and have identified hnRNP H as an abundant candidate. The specific binding of hnRNP H requires not only a CUG repeat expansion but also a splicing branch point distal to the repeats. Suppression of hnRNP H expression by RNAi rescued nuclear retention of RNA with CUG repeat expansions. The identification of hnRNP H as a factor capable of binding and possibly modulating nuclear retention of mutant DMPK mRNA may prove to be an important link in our understanding of the molecular mechanisms that lead to DM1 pathogenesis.
...
PMID:HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. 1602 11

In order to understand the involvement of specific muscles in congenital myotonic dystrophy type 1 (DM1), we studied the clinical manifestations, and the genetic effects on various tissues in 2 siblings with congenital DM1. The distal leg muscles were more severely involved than the thigh muscles, as seen in the skeletal muscle magnetic resonance imaging. Molecular genetic analysis of the myotonic dystrophy type 1 protein kinase showed an elongation of the CTG triplet repeats between 850 and 1400 in the leukocytes, skin, fat, tendon, and muscles. Muscle biopsies showed a significant difference in the fiber type distribution between these two congenital DM1 patients. One revealed a prominent involvement of the tibialis anterior muscle with a predominance of type 1 fibers, similar to those muscle fiber distributions in older congenital or classic DM1 patients, suggesting a neurotrophic influence during muscle development. Another revealed a predominance of type 2 fibers in all muscle specimens, and dystrophic changes were observed in the peroneus longus muscle indicating a delayed differentiation or maturation of muscle fibers. We conclude that despite nearly the same number of CTG repeats in the leukocytes, highly individual variability of muscle differentiation may occur at teenagers of congenital DM1 in addition to different pathological findings in various skeletal muscles of patients with congenital DM1.
...
PMID:Congenital myotonic dystrophy: variability in muscle involvement and histopathological process. 1659 79

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG expansion in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene. It has been hypothesized that the pathogenesis in DM1 is triggered by a toxic gain of function of the expanded DMPK RNA. This expanded RNA is retained in nuclear foci where it sequesters and induces alterations in the levels of RNA-binding proteins (RNA-BP). To model DM1 and study the implication of RNA-BP in CUG-induced toxicity, we have generated a Drosophila DM1 model expressing a non-coding mRNA containing 480 interrupted CUG repeats; i.e. [(CUG)20CUCGA]24. This (iCUG)480 transcript accumulates in nuclear foci and its expression leads to muscle wasting and degeneration in Drosophila. We also report that altering the levels of two RNA-BP known to be involved in DM1 pathogenesis, MBNL1 and CUGBP1, modify the (iCUG)480 degenerative phenotypes. Expanded CUG-induced toxicity in Drosophila is suppressed when MBNL1 expression levels are increased, and enhanced when MBNL1 levels are reduced. In addition, (iCUG)480 also causes a decrease in the levels of soluble MBNL1 that is sequestered in the CUG-containing nuclear foci. In contrast, increasing the levels of CUGBP1 worsens (iCUG)480-induced degeneration even though CUGBP1 distribution is not altered by the expression of the expanded triplet repeat. Our data supports a mechanism for DM1 pathogenesis in which decreased levels of MBNL and increased levels of CUGBP mediate the RNA-induced toxicity observed in DM1. Perhaps more importantly, they also provide proof of the principle that CUG-induced muscle toxicity can be suppressed.
...
PMID:MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. 1672 74

Expanded CUG repeats in the 3'-untranslated region (UTR) of the gene encoding myotonic dystrophy protein kinase (DMPK) cause myotonic dystrophy type 1 disease (DM1). The presence of such repeats has been found to impede gene expression at several levels in model systems. We took a bioinformatic approach to survey all human mRNA sequences for polymorphic CUG repeats. Our survey revealed that CUG repeats occur widely in various regions of mRNAs, with higher frequency in protein coding regions than 5'-UTRs or 3'-UTRs. About 30 genes were found to contain CUG repeats that are polymorphic in the number of repeats, suggesting the potential to expand or shrink. However, long polymorphic repeats were restricted to the 3'-UTR of the DMPK gene and the coding region of the ribosomal protein L14 gene. Using cell-free translation systems, we showed that extended CUG repeats can inhibit protein synthesis in vitro in the rabbit reticulocyte lysate, but not in wheat germ extracts, consistent with our previous finding of an interaction of CUG repeats with the protein kinase PKR. In transfected cells, CUG repeats can inhibit gene expression both in cis and in trans. However, observations with PKR-minus cells indicate that these effects are not primarily attributable to the interaction of extended CUG repeats with PKR. Northwestern blotting detected the presence in human cells of more CUG-binding proteins than are currently known.
...
PMID:Polymorphic CUG repeats in human mRNAs and their effects on gene expression. 1711 33

In myotonic dystrophy type 1 (DM1), triplet repeat expansion in the 3' untranslated region of dystrophia myotonica protein kinase (DMPK) causes the nuclear retention of mutant messenger RNA (mRNA). Although the DMPK gene locus positions precisely at the outer edge of a factor-rich SC-35 domain, the normal mRNA consistently accumulates within the domain, and this RNA is depleted upon transcriptional inhibition. In DM1, mutant transcripts detach from the gene but accumulate in granules that abut but do not enter SC-35 domains, suggesting that RNA entry into the domain is blocked. Despite their exclusion from these compartments, mutant transcripts are spliced. MBNL1 (muscleblind-like protein 1) is an alternative splicing factor that becomes highly concentrated with mutant RNA foci. Small interfering RNA-mediated knockdown of MBNL1 promotes the accumulation or entry of newly synthesized mutant transcripts in the SC-35 domain. Collectively, these data suggest that an initial step in the intranuclear path of some mRNAs is passage from the gene into an SC-35 domain and implicate these structures in postsplicing steps before export.
...
PMID:Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains. 1784 70

Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3'-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk-/-) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk-/- mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk-/- mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.
...
PMID:Role of myotonic dystrophy protein kinase (DMPK) in glucose homeostasis and muscle insulin action. 1798 20

Type I myotonic dystrophy (DM1) is caused by a triplet repeat expansion in the 3'-untranslated region (UTR) of the dystrophia myotonia protein kinase (DMPK) gene. Pathogenesis is closely linked with production of a toxic RNA from the mutant allele, which interferes with function of several RNA-binding proteins, including CUGBP1. Here we show that expression of a mutant DMPK 3'-UTR containing 960 CUG repeats is sufficient to increase expression and stability of an mRNA encoding the potent proinflammatory cytokine, tumor necrosis factor (TNF). CUGBP1 specifically recognizes sequences within the TNF 3'-UTR that are dissimilar from its canonical UG-rich binding site. Depletion of CUGBP1 from mouse myoblasts results in increased abundance of TNF mRNA through stabilization of the transcript. Moreover, activation of the protein kinase C pathway by treatment with phorbol ester, which has been shown previously to result in CUGBP1 phosphorylation, also causes TNF mRNA stabilization. Our results suggest that the elevated serum TNF seen in DM1 patients may be derived from muscle where it is induced by expression of toxic DMPK RNA. Importantly, overexpression of this potent cytokine could contribute to the muscle wasting and insulin resistance that are characteristic of this debilitating disease.
...
PMID:The RNA-binding protein CUGBP1 regulates stability of tumor necrosis factor mRNA in muscle cells: implications for myotonic dystrophy. 1855 47

DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3'-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)(n) or (CCUG)(n). The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.
...
PMID:Pathogenic mechanisms of myotonic dystrophy. 1990 63

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats at the 3'-UTR of the serine/threonine protein kinase DMPK. Expanded CTG repeats are toxic since they are transcribed into an RNA molecule which is then sequestered within the nucleus in the form of foci. RNA cytotoxicity is linked to the aberrant splicing of several developmentally regulated genes. DMPK transcripts undergo alternative splicing giving rise to many isoforms but do not seem to be involved in the splicing dysregulation of DM1. However, decreased levels of DMPK in DM1 patients and DMPK involvement in muscle weakness and cardiac dysfunction in animal models have been reported. The variability in phenotypic expression of DMPK together with its differential subcellular targeting, suggests that different splicing isoforms may be involved in different signalling pathways, possibly through DMPK-interacting proteins. To gain better insight into the DMPK function, we used mass spectrometry to identify proteins co-segregating with DMPK in soluble complexes isolated from high-speed supernatant of rat muscles. We carried out experiments with native DMPK to preserve the physiological stoichiometry with potential partners. DMPK-containing complexes were isolated and immuno-detected by non-denaturing electrophoresis, gel filtration, ionic-exchange chromatography and immunoprecipitation. DMPK peptides were identified by high-resolution mass spectrometry together with several putative DMPK-binding proteins, including several heat shock proteins such as HSP20/HSPB6, HSP60/CPN60, HSP70 and HSP90. We also obtained evidence of a direct interaction of DMPK with alphaB-crystallin/HSPB5 and HSP25/HSPB1.
...
PMID:Mass spectrometry analysis of complexes formed by myotonic dystrophy protein kinase (DMPK). 2018 67


<< Previous 1 2 3 4 5 6 7 8 Next >>

---