Disease relevance of SCYE1

• The N terminus of in vitro-processed EMAPII coincides exactly with that of the mature cytokine isolated from conditioned medium of fibrosarcoma cells [1].
• We investigated its effects on lymphocytes, using recombinant protein, or colorectal cancer cell lines, as a source of native EMAP-II [2].
• A single intra-tumor injection of EMAP II into Meth A sarcomas induced acute thrombohemorrhage and partial tumor regression [3].
• Systemic infusion of EMAP II into C3H/HeJ or Balb/c mice was associated with systemic toxicity, pulmonary congestion, and the appearance of TNF, interleukin-1 and -6 in the plasma [3].
• The similar structures to the RNA binding motif of EMAP II was previously observed in the anticodon binding domain of yeast Asp-tRNA synthetase (AspRSSC) and the B2 domain of Thermus thermophilus Phe-tRNA synthetase [4].

High impact information on SCYE1

• In growing capillary endothelial cultures, EMAP II induced apoptosis in a time- and dose-dependent manner, whereas other cell types were unaffected [5].
• These data suggest that EMAP II is a tumor-suppressive mediator with antiangiogenic properties allowing it to target growing endothelium and limit establishment of neovasculature [5].
• In a lung metastasis model, EMAP II blocked outgrowth of Lewis lung carcinoma macrometastases; total surface metastases were diminished by 65%, and of the 35% metastases present, approximately 80% were inhibited with maximum diameter <2 mm (P < 0.002 vs. controls) [5].
• Intraperitoneally administered EMAP II suppressed the growth of primary Lewis lung carcinomas, with a reduction in tumor volume of 65% versus controls (P < 0.003) [5].
• The low sequence homology between the extra domain of EMAPII and either its own OB fold or that of Trbps suggests that dimer mimicry originated from convergent evolution rather than gene duplication [6].

Chemical compound and disease context of SCYE1

• In parallel, we investigated the correlation of p43 expression in MCF-7 and T47-D breast cancer cell lines during proliferation induced by estradiol plus fetal calf serum (assessed by 3H-thymidine incorporation), compared to p43 expression in stationary non-stimulated cell cultures [7].
• The addition of indomethacin or levamisole did not influence this inhibitory effect of p43 in breast cancer patients [8].

Biological context of SCYE1

• Endothelial monocyte activating polypeptide II (EMAPII) is a cytokine that is specifically induced by apoptosis [9].
• Aminoacylation activity of RRS was enhanced about 2.5-fold by the interaction with pro-EMAPII but not with its N- or C-terminal domains alone [9].
• Neutrophils exposed to EMAP II demonstrated elevated cytosolic free calcium concentration, peroxidase generation, and chemotaxis [3].
• As a consequence, p43 compares well with a molecular fuse that triggers the irreversible cell growth/cell death transition induced under apoptotic conditions [1].
• Modulation of cellular phenotype by EMAP II-derived peptide was suggested by peptide-induced elevation of cytosolic free calcium concentration in fura-2-loaded MPs and PMNs and by stimulation of peroxidase release in PMNs [10].

Anatomical context of SCYE1

• EMAP II inhibited the growth of endothelial cells, and this effect was relieved by soluble alpha-ATP synthase [11].
• Thus, activated lymphocytes, along with proliferating endothelial cells, are targets for the cytotoxic activity of EMAP-II [2].
• Recombinant EMAP-II inhibits DNA synthesis and cell division, and induces apoptosis in mitogen-activated lymphocytes in PBMC preparations, and in Jurkat T cells [2].
• Translation arrest is accompanied by the release of the EMAPII cytokine that plays a role in the engulfment of apoptotic cells by attracting phagocytes [1].
• p43 is one of the three auxiliary components invariably associated with nine aminoacyl-tRNA synthetases as a multienzyme complex ubiquitous to all eukaryotic cells from flies to humans [12].

Associations of SCYE1 with chemical compounds

• Local injection of EMAP II into a tumor resistant to the effects of TNF, murine mammary carcinoma, rendered it sensitive to subsequently administered TNF, which resulted in acute thrombohemorrhage and partial regression [3].
• The sequence of several proEMAP II proteins suggests that the p43 component of the complex is the precursor of the active mature cytokine after cleavage at a conserved Asp residue [12].
• Based on the NH2-terminal protein sequence, a full-length cDNA has been cloned which indicates that the precursor of EMAP II is a unique, leaderless, single polypeptide chain with predicted molecular mass approximately 34 kDa and that the mature form released by Meth A cells corresponds to approximately 20 kDa [3].
• Cross-linking of 125I-EMAP II-derived peptide (residues 12-20) by disuccinimidyl suberate to human MPs demonstrated a band, approximately 73 kDa, on reduced sodium dodecyl sulfate-polyacrylamide gel electrophoresis [10].
• Incubation of fresh endometrial tissue (n = 5) with 3 micro g/ml indomethacin resulted in an increase in EMAP II protein expression, compared with control untreated tissue [13].

Physical interactions of SCYE1

• Herein, we have demonstrated that the N-terminal domain of pro-EMAPII interacts with the N-terminal extension of human cytoplasmic arginyl-tRNA synthetase (RRS) using genetic and immunoprecipitation analyses [9].

Regulatory relationships of SCYE1

• SiRNA to DOC1 completely abolished EMAP-II stimulated gene expression of DOC1 [14].
• The inhibitors for protein kinase C (PKC) and phospholipase C (PLC) prevented the p43-induced TNF production [15].
• Finally, we used sequence analysis to exclude mutations in the coding region of two candidate genes, bone morphogenetic protein type II receptor (BMPR2) and endothelial monocyte-activating polypeptide II (EMAP II), as candidates for ACD [16].

Other interactions of SCYE1

• Moreover, their expression inversely correlates with tumor diameter and with RARS expression (P < 0.05), but directly correlates with p43 secretion (P < 0.02) [17].
• Among these genes, downregulated in ovarian cancer 1 (DOC1) gene was studied further because of its possible role in EMAP-II induced cytoskeletal remodeling [14].
• The p43 protein is associated with human macromolecular aminoacyl tRNA synthetase complex and secreted to up-regulate diverse proinflammatory genes including TNF [15].
• Interaction of the C-terminal domain of p43 and the alpha subunit of ATP synthase. Its functional implication in endothelial cell proliferation [11].
• CONCLUSIONS: These data suggests a novel function for EMAP II and a hitherto undescribed role of the CXCR3 chemokine receptor in EPC recruitment [18].

Analytical, diagnostic and therapeutic context of SCYE1

• The interaction of EMAP II and alpha-ATP synthase was confirmed by enzyme-linked immunosorbent assay and in vitro pull down assays and blocked with the antibodies raised against EMAP II and alpha-ATP synthase [11].
• In situ hybridization and immunohistochemistry localized EMAP II mRNA and protein expression in glandular epithelial, endothelial, and stromal cells in the functionalis and basalis layers of the endometrium [13].
• The temporal pattern of EMAP II expression was confirmed further by Western blotting; EMAP II protein expression was detected as a 43-kDa band [13].
• In the present study, cDNA array analysis has identified endothelial monocyte-activating polypeptide II (EMAP II) as a PGE(2)-regulated gene in endometrial epithelial cells [13].
• Coculture with DLD-1 colorectal cancer cells or media conditioned by these cells induces apoptosis in Jurkat cells, which is partially reversed by antibodies against EMAP-II [19].

References