Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three different cDNA clones, namely DM1-1, Dah1, and Dah2, encoding hepatic cytochrome P-450, were isolated from a cDNA library in lambda gt11 constructed from liver RNA of polychlorinated biphenyl-treated beagle dogs. DM1-1 was 1857 base pairs (bp) long and encoded a polypeptide of 457 residues. Dah1 was 2394 bp long and contained an entire coding region for 524 amino acid residues. In addition, Dah2 was 1623 bp long and had an open reading frame consisting of 503 amino acid residues, although it lacked the translational initiation codon. Judging from the similarity of the nucleotide and amino acid sequences, forms of cytochrome P-450 encoded by DM1-1, Dah1, and Dah2 were judged to belong to the P450IIC, P450IA1, and P450IA2 subfamilies, respectively. Northern blot analysis of RNA from various tissues, using the specific 3' noncoding regions of Dah1 and Dah2 as probes, indicated that mRNAs for P-450(Dah1) and P-450(Dah2) were not detectable in tissues from untreated dogs, except for P-450(Dah2) in livers. Polychlorinated biphenyl induced both mRNAs in liver, kidney, and lung, especially in the kidney.
Mol Pharmacol 1990 Nov
PMID:Isolation of cDNAs coding for three different forms of liver microsomal cytochrome P-450 from polychlorinated biphenyl-treated beagle dogs. 212 30

The trinucleotide repeat sequences which become unstable in fragile X syndrome and myotonic dystrophy are located in the untranslated regions of their respective genes, FMR1 and DM1. This implies that a functional constraint other than coding capacity maintains the presence of the repeats. In the case of fragile X syndrome, sequences adjacent to the repeat are methylated in affected individuals and the FMR1 gene is transcriptionally inactive. We demonstrate that the fragile X p(CCG)n repeat itself is methylated in vivo and that methylation of this repeat is able to inhibit in vitro binding of a novel, specific nuclear p(CCG)n binding protein (CCG-BP1)--one of at least 10 distinct simple tandem repeat sequence binding proteins (STR-BPs). We describe additional, apparently distinct, binding activities both for the methylated form of the p(CCG)n repeat and for each of the single strands of the repeat.
Hum Mol Genet 1993 Sep
PMID:Fragile X syndrome unstable element, p(CCG)n, and other simple tandem repeat sequences are binding sites for specific nuclear proteins. 824 66

Myotonic dystrophy type 1 (DM1) is one of a growing number of inherited human diseases whose molecular basis has been implicated as the expansion of a trinucleotide DNA repeat. Expanded disease-associated alleles of >50 CTG repeats are unstable in both the germline and soma. Expansion of the unstable alleles over time and variation of the level of mutation between the somatic tissues of an individual are thought to account at least partially for the tissue specificity and progressive nature of the symptoms. We previously generated a number of transgenic mouse lines containing a large expanded CTG repeat tract that replicated a number of the features of unstable DNA in humans, including frequent sex-specific changes in allele length during intergenerational transmission. Small length change mutations were apparent in the somatic tissues of young mice in all of the lines generated, but the gross instability observed in human DM1 patients was not replicated. We now show that in one of the lines, Dmt -D, spectacular, expansion-biased, tissue-specific instability is observed in older mice. The highest levels of instability were detected in kidney with gains of >500 repeats, representing a tripling of allele length, in some cells. Mosaicism accumulated in an age-dependent manner, but the tissue specificity did not obviously correlate with cell turnover. Such gross somatic mosaicism was not observed in three other lines examined, further emphasizing a role for flanking DNA in modulating repeat stability.
Hum Mol Genet 2000 Feb 12
PMID:Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a transgenic mouse model of triplet repeat instability. 1065 54

In myotonic dystrophy type 1 (DM1), an expanded CTG repeat shows repeat size instability in somatic and germ line tissues with a strong bias toward further expansion. To investigate the mechanism of this expansion bias, 29 DM1 and six normal lymphoblastoid cell lines (LBCLs) were single-cell cloned from blood cells of 18 DM1 patients and six normal subjects. In all 29 cell lines, the expanded CTG repeat alleles gradually shifted toward further expansion by "step-wise" mutations. Of these 29 cell lines, eight yielded a rapidly proliferating mutant with a gain of large repeat size that became the major allele population, eventually replacing the progenitor allele population. By mixing cell lines with different repeat expansions, we found that cells with larger CTG repeat expansion had a growth advantage over those with smaller expansions in culture. This growth advantage was attributable to increased cell proliferation mediated by Erk1,2 activation, which is negatively regulated by p21(WAF1). This phenomenon, which we designated "mitotic drive" , is a novel mechanism which can explain the expansion bias of DM1 CTG repeat instability at the tissue level, on a basis independent of the DNA-based expansion models. The lifespans of the DM1 LBCLs were significantly shorter than normal cell lines. Thus, we propose a hypothesis that DM1 LBCLs drive themselves to extinction through a process related to increased proliferation.
Hum Mol Genet 2001 Apr 01
PMID:"Mitotic drive" of expanded CTG repeats in myotonic dystrophy type 1 (DM1). 1128 51

C242-DM1 is a tumor-activated immunotoxin under development by GlaxoSmithKline plc (formerly SmithKline Beecham plc), under licence from ImmunoGen Inc, as a potential treatment for colon tumor. It consists of a colon cancer-specific humanized antibody, C242, conjugated to the maytansine derivative DM1. In preclinical studies, C242-DM1 caused complete tumor regression in animal models of both human pancreatic and non-small cell lung cancer (NSCLC) at non-toxic doses. C242-DM1 has also been evaluated in an immunoconjugate combination with J-591 (Cornell University). The J591-DM1 immunoconjugate demonstrated effective, antigen-specific delivery of a highly cytotoxic drug to PSMA-positive Pca cells in vitro and in vivo with low systemic toxicity. Results from studies in monkeys showed that C242-DM1 had no significant toxicity or side effects, when administered at doses higher than those that were previously shown to completely eradicate human colon tumors in mice [271420]. ImmunoGen acquired the right to evaluate, and an option to license, technology related to maytansines from Takeda. In February 1999, ImmunoGen and SmithKline Beecham signed a US $45 million development and commercialization agreement for C242-DM1 [313493]. In August 1997, Immunogen received an SBIR grant to advance development of huC242-DM1 [258356]. EP-00425235, held by ImmunoGen, covers conjugated forms of ansamitocin (maytansine) derivatives. Takeda holds several patents for the production of ansamitocin and its analogs, the first one being JP-53124692.
Curr Opin Mol Ther 2001 Apr
PMID:Technology evaluation: C242-DM1, ImmunoGen Inc. 1133 34

Myotonic dystrophy type 1 (DM1) is a dominant neuromuscular disorder caused by a trinucleotide (CTG) repeat expansion. Mutant DMPK 3'-untranslated region (3'-UTR) transcripts aggregate in nuclear foci and are thought to impose dominant-negative effects by interacting with RNA binding proteins. We demonstrated previously that the mutant 3'-UTR RNA disrupted C2C12 myoblast differentiation, and that the CUG expansion was necessary for this effect. Several proteins are known to interact with the CUG tract or the region 3' (distal) to it. Here, using a library of transfected C2C12 clones, we show that although transcripts containing a CUG expansion alone or a CUG expansion plus the distal region of the DMPK 3'-UTR accumulate into RNA foci, neither of these RNAs affect C2C12 myogenesis. Thus, RNA foci formation, and perturbation of any RNA binding factors involved in this process, are not sufficient to block myoblast differentiation. Interestingly, we found that transcripts containing expanded CUG tracts can form both nuclear and cytoplasmic RNA foci, demonstrating that factors involved in foci formation are present in the nucleus and cytoplasm. RNA analysis of myogenic markers revealed that the mutant DMPK 3'-UTR mRNA does not affect myoblast determination factors MyoD or Myf5, but significantly impedes upregulation of the differentiation factors myogenin and p21. C2C12 provide a good model to study adult muscle regeneration. Our observations in this system may be relevant to the lack of a regenerative response to continued muscle wasting in DM, and point to defects in early events in the myogenic response to muscle damage.
Hum Mol Genet 2001 Sep 01
PMID:The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. 1155 24

Hexokinase coding DM1 and DM2 sequences were obtained from genomic DNA of a Drosophila melanogaster cell line by PCR amplification strategy. Both the sequences were found to encode an enzyme with a molecular weight of 50,000 Da. Amino acid sequence alignment of DM1 and DM2 shows approximately 45% homology with yeast and human hexokinases. The sequences also indicated the presence of conserved amino acid residues and motifs that are present in mammalian hexokinases and are involved in the binding of different substrates. Southern blot analysis suggests that the D. melanogaster genome contain a single copy of DM1 and DM2 sequences. Northern analysis indicates DM1 is expressed as more than one transcript in adult as well as in the D.Mel2 cell line. DM2 is expressed as a single transcript in adult flies. Expression levels for DM1 and DM2 encoded message were found to be similar in different stages of development as seen by RT-PCR. The biotechnological significance of these sequences in metabolic engineering of cells is discussed.
Insect Biochem Mol Biol 2001 Nov 01
PMID:Cloning of two hexokinase isoenzyme sequences from Drosophila melanogaster. 1158 29

Intraneuronal aggregates of hyperphosphorylated tau proteins, referred to as pathological tau, are found in brain areas of demented patients affected by numerous different neurodegenerative disorders. We previously described a particular biochemical profile of pathological tau proteins in myotonic dystrophy type 1 (DM1). This multisystemic disorder is characterized by an unstable CTG repeat expansion in the 3'-untranslated region of the DM protein kinase gene. In the human central nervous system, tau proteins consist of six isoforms that differ by the presence or absence of the alternatively spliced exons 2, 3 and 10. Here we show that the pattern of tau isoforms aggregated in DM1 brain lesions is characteristic. It consists mainly of the aggregation of the shortest human tau isoform. A disruption in normal tau isoform expression consisting of a reduced expression of tau isoforms containing the exon 2 was observed at both the mRNA and protein levels. Large expanded CTG repeats were detected and showed marked somatic heterogeneity between DM1 cases and in cortical brains regions analysed. Our data suggest a relationship between the CTG repeat expansion and the alteration of tau expression showing that DM1 is a peculiar tauopathy.
Hum Mol Genet 2001 Sep 15
PMID:Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. 1159 Jan 31

The phenotypes in myotonic dystrophy types 1 and 2 (DM1 and DM2) are similar, suggesting a shared pathophysiologic mechanism. DM1 is caused by expansion of a CTG repeat in the DMPK gene. Pathogenic effects of this mutation are likely to be mediated, at least in part, by the expanded CUG repeat in mutant mRNA. The mutant transcripts are retained in the nucleus in multiple discrete foci. We investigated the possibility that DM2 is also caused by expansion of a CTG repeat or related sequence. Analysis of DNA by repeat expansion detection methods, and RNA by ribonuclease protection, did not show an expanded CTG or CUG repeat in DM2. However, hybridization of muscle sections with fluorescence-labeled CAG-repeat oligonucleotides showed nuclear foci in DM2 similar to those seen in DM1. Nuclear foci were present in all patients with symptomatic DM1 (n = 9) or DM2 (n = 9) but not in any disease controls or healthy subjects (n = 23). The foci were not seen with CUG- or GUC-repeat probes. Foci in DM2 were distinguished from DM1 by lower stability of the probe-target duplex, suggesting that a sequence related to the DM1 CUG expansion accumulates in the DM2 nucleus. Muscleblind proteins, which interact with expanded CUG repeats in vitro, localized to the nuclear foci in both DM1 and DM2. These results support the idea that nuclear accumulation of mutant RNA is pathogenic in DM1, suggest that a similar disease process occurs in DM2, and point to a role for muscleblind in the pathogenesis of both disorders.
Hum Mol Genet 2001 Sep 15
PMID:Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. 1159 Jan 33

The autosomal dominant mutation causing myotonic dystrophy (DM1) is a CTG repeat expansion in the 3'-UTR of the DM protein kinase (DMPK) gene. This multisystemic disorder includes myotonia, progressive weakness and wasting of skeletal muscle and extramuscular symptoms such as cataracts, testicular atrophy, endocrine and cognitive dysfunction. The mechanisms underlying its pathogenesis are complex. Recent reports have revealed that DMPK gene haploinsufficiency may account for cardiac conduction defects whereas cataracts may be due to haploinsufficiency of the neighboring gene, the DM-associated homeobox protein (DMAHP or SIX5) gene. Furthermore, mice expressing the CUG expansion in an unrelated mRNA develop myotonia and myopathy, consistent with an RNA gain of function. We demonstrated that transgenic mice carrying the CTG expansion in its human DM1 context (>45 kb) and producing abnormal DMPK mRNA with at least 300 CUG repeats, displayed clinical, histological, molecular and electrophysiological abnormalities in skeletal muscle consistent with those observed in DM1 patients. Like DM1 patients, these transgenic mice show abnormal tau expression in the brain. These results provide further evidence for the RNA trans-dominant effect of the CUG expansion, not only in muscle, but also in brain.
Hum Mol Genet 2001 Nov 01
PMID:Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. 1172 59


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