Disease relevance of DMN

• Expression of the intermediate filament protein synemin in myofibrillar myopathies and other muscle diseases [1].
• The desmuslin protein interacts with and is closely related to desmin, a protein encoded by a locus mutated in some forms of hereditary distal myopathy [2].
• These results are consistent with nicotine modulating feeding behavior and body weight, in part, by affecting CART transcript levels in the DMN, PVN and/or PE [3].
• Taken together with synemin localization within ruffled membranes, this finding suggests that synemin plays a role in motility of glioblastoma cells [4].
• Intermediate filament protein synemin is present in human reactive and malignant astrocytes and associates with ruffled membranes in astrocytoma cells [4].

High impact information on DMN

• These data suggest that this high molecular weight protein is closely associated with desmin and vimentin filaments in muscle cells; to indicate this, we have named the protein synemin, from the Greek oa uv (with) and v eta mu alpha (filament) [5].
• The examples used were 1) exposure to DES and mammary carcinoma and 2) exposure to DMN and liver carcinoma [6].
• Measurable CO2 was formed by bronchial explants from: 1) DMN, DEN, and NPy in all 4 patients; 2) DNP in 3 of 4 patients; and 3) NPd in only 1 of 4 patients [7].
• Sequence analysis revealed that DMN has a short N-terminal domain, a conserved rod domain, and a long C-terminal domain, all common features of type 6 intermediate filament proteins [8].
• Our findings suggest that DMN may serve as a direct linkage between the extracellular matrix and the Z-discs (through plectin) and may play an important role in maintaining muscle cell integrity [8].

Chemical compound and disease context of DMN

• Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, inhibited the genotoxic effects of N-nitrosodimethylamine (DMN) and of 2-amino-1-methyl-6-phenylimidazo[4,5-beta]pyridine (PhIP) in differential DNA repair assays with E. coli K-12 strains in vitro and in animal mediated assays with mice [9].
• The acute toxicity of N-nitrosodimethylamine (DMN) and N-nitrosodiethylamine (DEN) was determined for three groups of aquatic organisms: algae, invertebrates, and fish [10].

Biological context of DMN

• RESULTS: The desmuslin gene was localized to chromosome 15q26.3 by electronic screening of the human DNA sequence database [2].
• Primer pairs were designed to amplify the 5 exons of the desmuslin gene in 11 overlapping DNA segments [2].
• Genomic organization and single-nucleotide polymorphism map of desmuslin, a novel intermediate filament protein on chromosome 15q26.3 [2].
• Transfection studies indicate that synemin requires the presence of another IF protein, such as vimentin, in order to assemble into IFs [11].
• Our previous studies (Bellin, R. M., Sernett, S. W., Becker, B., Ip, W., Huiatt, T. W., and Robson, R. M. (1999) J. Biol. Chem. 274, 29493-29499) demonstrated that synemin forms heteropolymeric IFs with major IF proteins and contains a binding site for the myofibrillar Z-line protein alpha-actinin [12].

Anatomical context of DMN

• Immunofluorescent microscopy localizes DMN in a stripe-like pattern in longitudinal sections and in a mosaic pattern in cross sections of skeletal muscle [8].
• These results indicate that synemin is an important IF protein in muscle cells that helps fortify the linkage between the peripheral layer of cellular myofibrils and the costameric regions located along the sarcolemma and the sarcolemma region located within the neuromuscular and myotendinous junctions (NMJs and MTJs) [13].
• In normal rat and human livers, synemin immunoreactivity was found in HSCs, smooth muscle cells of hepatic arterioles, and nerve bundles in portal tracts, but not in portal fibroblasts [14].
• CONCLUSIONS: Synemin forms heteropolymeric filaments with type-III IF proteins and acts as a bridging protein between IFs and a specific type of focal adhesions [14].
• Low-resolution immunohistochemical analysis localizes beta-synemin within muscle along the sarcolemma, whereas confocal microscopic analysis further refines localization to the costamere and muscle Z-lines [15].

Associations of DMN with chemical compounds

• In contrast, nine days of nicotine treatment reduced CART levels in the DMN as compared to saline controls [3].
• Binding levels of DNP were as high as those with the two acyclic N-nitrosamines DMN and DEN, but binding levels of NPy and NPd were lower [7].
• The actions of menadione on ROS production and cell fate were compared with those of a non-cycling analogue (2,4-dimethoxy-2-methylnaphthalene (DMN)) using real-time confocal microscopy of isolated perfused murine pancreatic acinar cells [16].
• Furthermore, bile acid (taurolithocholic acid 3-sulfate)-induced caspase activation was also greatly increased by DMN, whereas DMN had no effect per se [16].
• A small amount of a nitrosamine, N-nitrosodimethylamine (DMN), was detected in the stomach after a single dose of NaNO2 [17].

Physical interactions of DMN

• By utilizing blot overlay assays, we show herein that synemin also interacts with the costameric protein vinculin [12].

Co-localisations of DMN

• Electron microscopic analysis shows DMN colocalized with desmin at the Z-lines [8].
• In ruffled membranes, synemin was found to co-localize with alpha-actinin [4].

Regulatory relationships of DMN

• Analysis of endogenous protein expression in SW13 clonal lines reveals that synemin is coexpressed and colocalized with vimentin IFs in SW13.C1 vim+ cells but is absent in SW13.C2 vim- cells [11].
• DMN produced no change in reactive oxygen species per se but significantly potentiated menadione-induced effects, probably via enhancement of one-electron reduction, since DMN was found to inhibit NAD(P)H:quinone oxidoreductase detoxification [16].

Other interactions of DMN

• Interactions of intermediate filament protein synemin with dystrophin and utrophin [13].
• Co-transfection and immunolabeling experiments indicate that both synemin isoforms are incorporated with desmin to form heteropolymeric IFs [18].
• Of patients affected by MM, two showed the presence of mutations in the desmin gene; none had mutations in the alphaB-crystallin gene; and no mutations were identified in synemin or syncoilin genes of three patients [1].
• METHODS: In isolated and cultured rat HSCs, synemin expression was examined by quantitative reverse transcriptase polymerase chain reaction, western blotting, and immunocytochemistry [14].
• The C-terminal approximately 300-amino acid region of synemin binds to the N-terminal head and central rod domains of alpha-actinin and the approximately 150-amino acid C-terminal tail of vinculin [12].

Analytical, diagnostic and therapeutic context of DMN

• By Northern blot analysis, we find that DMN is expressed mainly in heart and skeletal muscle, although there is some expression in brain [8].
• In human and rat liver tissue, the presence of synemin was investigated by immunohistochemistry [14].
• Protein-protein interaction between synemin and possible binding partners was investigated by co-immunoprecipitation and confocal microscopy [14].
• Western blotting shows that astrocytic tumors contain greater amounts of alpha-synemin than do normal brain tissues [4].
• Cryostat sections and established in vitro cultures of dimethylnitrosamine(DMN)-induced renal mesenchymal tumours and monolayer cultures of transformed kidney cells derived from rats treated with a carcinogenic dose of DMN were examined by indirect immunofluorescence with human serum containing smooth muscle antibody [19].

References