Disease relevance of Mup2

• The mouse M2 protein sequence was quite homologous to the equivalent protein in the clam Spisula solidissima, while the homology to the smaller subunits of Epstein-Barr virus, herpes simplex virus type 2, and Escherichia coli ribonucleotide reductases were less pronounced [1].
• In studies reported here, we compared the expression of the genes that code for the M1 and M2 subunits of ribonucleotide reductase in S49 cells, which are arrested in G1 phase by agents that increase cyclic AMP, with those from CEM human T lymphoma cells that are unaffected by exposure to dibutyryl cyclic AMP [2].
• Dendritic cells presenting pyruvate kinase M1/M2 isozyme peptide can induce experimental allergic myositis in BALB/c mice [3].
• The M2 gene was 2155 nucleotides in length and was predicted to encode muB major outer capsid protein of 676 amino acids [4].
• It was unexpectedly found that 5'-termini of the M1 and M2 genes ended with 5'-ACUUUU and 5'-UCUUUU, respectively, instead of 5'-GCUUUU, which is present on most mRNAs of other avian reoviruses (ARV) [4].

High impact information on Mup2

• The mammalian enzyme also consists of two nonidentical subunits (M1 and M2), only one of which (M1) has been obtained in pure form [5].
• We propose that resistance to hydroxyurea is caused either by overproduction of the complete M2 subunit or by increased generation of the tyrosine radical within the M2 protein [5].
• The amount of M2 protein could not be measured directly, but the M2 activity in extracts from resistant cells (but not normal cells) showed an EPR spectrum very similar to that of the tyrosine radical of the bacterial B2 subunit [5].
• Of importance, purified tumor-associated macrophages display a similar M2 phenotype and are suppressive for antitumor CTLs, via a mechanism that can be almost completely reversed by PPARgamma ligands [6].
• In C57BL/6J mice, MUP 2 and MUP 4 are known to be synthesized in male, but not female, liver, and MUP 3 is known to be synthesized in both male and female liver and mammary gland [7].

Chemical compound and disease context of Mup2

• Vaccinia virus mutants selected for the ability to grow in high concentrations of a specific inhibitor of ribonucleotide reductase, hydroxyurea, amplified the M2 gene and harbored tandem arrays (2 to 15 copies) of the gene within the HindIII F region [8].

Biological context of Mup2

• The complete nucleotide sequence of the 2,111-base-pair-long M2 cDNA revealed an open reading frame coding for 390 amino acids, which corresponds to a molecular weight of 45,100 [1].
• Expression of M2 protein could be demonstrated by electron paramagnetic resonance spectroscopy after transfection of COS-7 monkey cells with the plasmid [1].
• We have isolated expressible cDNA clones of both subunits from an Okayama-Berg cDNA library made with mRNA from hydroxyurea-resistant, M2 protein-overproducing mouse TA3 cells [1].
• Mammalian ribonucleotide reductase consists of two nonidentical subunits, proteins M1 and M2, which are differentially regulated during the cell cycle [1].
• In patients, biotransformation represented the predominant mechanism of drug clearance with as much as 80% of a low dose (0.5 g/m2) recovered in urine as M1 and M2 after only 6 h [9].

Anatomical context of Mup2

• Early increases in M1 and/or M2 message and protein levels were observed only in malignant cell lines [10].
• CD8+ T cells play a major role in recovery from the primary infection, and also in regulating latently infected cells expressing the M2 gene product [11].
• Only when we inoculated syngeneic bone marrow-derived DC presenting pyruvate kinase M1/M2 peptide 464-472 in BALB/c mice, 41.7% of the mice (EAM) developed pathological changes in skeletal muscle compatible to human PM [3].
• Transient elevation of ribonucleotide reductase activity, M2 mRNA and M2 protein in BALB/c 3T3 fibroblasts in the presence of 12-O-tetradecanoylphorbol-13-acetate [12].
• Ability to attach to the reconstituted basement membrane (Matrigel) was higher for clone H than clone L during an observation period of 30-60 min, whereas clones M1 and M2 were found to be intermediate in ability [13].

Associations of Mup2 with chemical compounds

• Taurine conjugation reaction of unchanged Am-80 and hydroxy-Am-80 (to form M-6 and both M-1 and M-2, respectively) was distinct in rats and dogs, but, hardly detected in mice and rabbits [14].
• Metabolite 2 (M2) was also a glucuronide (Mr 456) but appeared to be an unusual isomer of M1 [9].
• Mice cleared flavone acetic acid much more slowly than patients (289 ml/h/m2 after 600 mg/m2 i.p. versus 2.3 liters/h/m2 after 4.8 g/m2-1-h i.v. infusion) without producing M1 or M2 [9].
• The time course of diminution of the M2 message concentration by dibutyryl cyclic AMP in S49 cells is similar to that obtained when cells are treated with actinomycin D and to the combination of the two agents [2].
• Under other conditions (when we inoculated DC presenting no synthetic peptides into BALB/c or C57BL/6 mice and DC presenting pyruvate kinase M1/M2 peptide into C57BL/6 mice), there were no necrotizing and inflammatory lesions [3].

Other interactions of Mup2

• On the other hand, tissue-type plasminogen activator was highest in clone M2 and low in both clones H and L [13].
• However, as in the first, differences in the metabolic detoxification of BD as reflected in relative amounts of the M1 and M2 urinary metabolites were associated with genotypes, this time both GST and EH [15].
• Expression of GH receptor and major urinary protein 2, a gene regulated by GH with STAT5b dependence, was decreased by MC at the mRNA level [16].

Analytical, diagnostic and therapeutic context of Mup2

• However, a Southern blot analysis of the corresponding genomic DNA sequences showed that the M2 gene was amplified fivefold but the M1 gene was still single copy [1].
• This was accompanied by an increase in protein M2 activity as shown by activity titration experiments [17].
• This report documents the first sequence analysis of the entire M1, M2, and M3 genome segments of the muscovy duck reovirus (DRV) S14 [4].
• All cell lines contained increased ribonucleotide reductase activity, elevated levels of the M2 component of ribonucleotide reductase as judged by electron paramagnetic resonance spectroscopy, and increased copies of M2 mRNA as determined by Northern blot analysis [18].
• The results suggest a novel role of M2 in the pupillary dilation, contrary to the well known cholinergic constriction [19].

References