Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated a 725-bp full-length cDNA clone for the human eosinophil cationic protein (ECP). ECP is a small, basic protein found in the matrix of the eosinophil's large specific granule that has cytotoxic, helminthotoxic, and ribonuclease activity, and is a member of the ribonuclease multigene family. The cDNA sequence shows 89% sequence identity with that reported for the related granule protein, eosinophil-derived neurotoxin (EDN). The open reading frame encodes a previously unidentified 27-amino acid leader sequence preceding a 133-residue mature ECP polypeptide with a molecular mass of 15.6 kD. The encoded amino acid sequence of ECP shows 66% identity to that of EDN and 31% identity to that of human pancreatic ribonuclease, including conservation of the essential structural cysteine and cataytic lysine and histidine residues. mRNA for ECP was detected in eosinophil-enriched peripheral granulocytes and in a subclone of the promyelocytic leukemia line, HL-60, induced toward eosinophilic differentiation with IL-5. No ECP mRNA was detected in uninduced HL-60 cells, or in HL-60 cells induced toward monocytic differentiation with vitamin D3 or toward neutrophilic differentiation with DMSO. In contrast, mRNA for EDN was detected in uninduced HL-60 cells and was upregulated in HL-60 cells induced with DMSO. Despite similarities in sequence and cellular localization, these results suggest that ECP and EDN are subject to different regulatory mechanisms.
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PMID:Human eosinophil cationic protein. Molecular cloning of a cytotoxin and helminthotoxin with ribonuclease activity. 247 57

We have isolated a unique genomic fragment encoding human ribonuclease 4 (RNase 4) of the mammalian ribonuclease gene family, whose members include pancreatic ribonuclease, eosinophil-derived neurotoxin, eosinophil cationic protein and angiogenin. We have determined that the coding sequence of RNase 4 resides on a single exon found on human chromosome 14. The mRNA encoding RNase 4 was detected by Northern analysis in a number of human somatic tissues, including pancreas, lung, skeletal muscle, heart, kidney and placenta, but not brain; liver represents the most abundant source. Interestingly, the mRNA encoding RNase 4 is approximately 2 kb in length, which is approximately twice as large as the mRNAs encoding other members of this gene family. A larger (approximately 2.4 kb), second transcript was detected in hepatic, pancreatic and renal tissues. The approximately 2 kb RNase 4 mRNA was detected in cells of the human promyelocytic leukemia line, HL-60, that had been treated with dibutyryl-cAMP to promote neutrophilic differentiation. In contrast, no mRNA encoding RNase 4 could be detected in cells treated with phorbol myristic acid (PMA), an agent promoting differentiation toward monocyte/macrophages, suggesting the existence of elements regulating tissue specific expression of this gene.
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PMID:Human ribonuclease 4 (RNase 4): coding sequence, chromosomal localization and identification of two distinct transcripts in human somatic tissues. 750 48

We evaluated two independent models of eosinophil differentiation for their ability to synthesize the ribonuclease toxins eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP). Cells from the clone 15 subline of HL-60 (human promyelocytic leukemia) produced both EDN and ECP; production of EDN increased in response to butyric acid (BA). CD34+ peripheral blood progenitor cells (PBPCs) grown with cytokines promoting eosinophil differentiation also produced EDN. EDN from both the clone 15 and PBPCs was more heterogeneous and heavily glycosylated (approximately 22-45 kDa) than EDN from the mature peripheral blood eosinophils (18-25 kDa). The heterogeneity of EDN from the clone 15 cells was not altered by endoglycosidase Hf, whereas treatment with peptide-N-glycosidase F (PNGase F) produced a single-band immunoreactive band (approximately 15 kDa). In contrast, only the highest molecular weight forms of EDN from differentiated PBPCs were eliminated by PNTGase F (reduced to 22-35 kDa), suggesting the presence of uncharacteristic forms of posttranslational modification. Synthesis of hyperglycosylated proteins has not been previously reported in PBPCs and is a feature shared with tumor cells and cell lines.
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PMID:Hyperglycosylation of eosinophil ribonucleases in a promyelocytic leukemia cell line and in differentiated peripheral blood progenitor cells. 761 5

The eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are both small, cationic ribonuclease toxins that are stored in and secreted by activated human eosinophilic leukocytes. We have previously shown that optimal expression of the EDN gene is dependent on an interaction between an intronic enhancer element or elements and the 5' promoter region. Here we present evidence demonstrating that the gene encoding ECP is regulated in an analogous fashion and that an intronic enhancer element functioning in both genes is a consensus binding sequence for the transcription factor NFAT-1. Our initial results demonstrate that one or more nuclear proteins isolated from human promyelocytic leukemia (HL-60) cells bind specifically at this consensus site (5'-GGAGAA-3') within the intron of the EDN gene and that disruption of this sequence reduced the characteristic 20-30-fold increase in reporter gene activity observed with the tandem EDN promoter/exon 1/intron construct to background levels. The NFAT-1 consensus site in the ECP gene differs from that found in the EDN gene by a single nucleotide (5'-GGAGAG-3'); the conversion of the 3' G to an A resulted in a further enhancement of the reporter gene activity supported by the ECP promoter/exon 1/intron construct. Interestingly, no "supershift" was observed in gel shift assays performed in the presence of anti-NFAT-1 antiserum, suggesting that a nuclear protein other than NFAT-1 may be acting at this consensus site.
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PMID:Intronic enhancer activity of the eosinophil-derived neurotoxin (RNS2) and eosinophil cationic protein (RNS3) genes is mediated by an NFAT-1 consensus binding sequence. 899 43

Onconase (Onc), a ribonuclease from oocytes or early embryos of Northern Leopard frog (Rana pipiens), is cytostatic and cytotoxic to a variety of tumor lines in vitro, inhibits growth of tumors in animal in vivo models and is currently in Phase IIIb clinical trials for malignant mesothelioma where it displays antitumor activity with minor overall toxicity to the patient. One of the characteristic features of Onc is a synergism with a variety of other antitumor modalities. Cepharanthine (Cep), a biscoclaurine alkaloid from Stephania cepharantha Hayata, is widely used in Japan to treat variety of ailments. It also shows low toxicity to patients. The aim of the present study was to assess the interaction of these two drugs on different tumor cell lines. When human promyelocytic leukemia HL-60, histiomonocytic lymphoma U937, multiple myeloma RPMI-8228, prostate carcinoma DU 145 and prostate adenocarcinoma LNCaP cells were exposed to relatively low concentrations of Onc or Cep their growth rates were somewhat suppressed but the cells were still able to proliferate. Cell growth, however, was totally abolished in each of these cell lines when treated with Onc and Cep combined. The frequency of apoptosis was also many-fold higher in cultures treated with a combination of Onc and Cep than in respective cultures treated with Onc or Cep alone. The mechanism of the observed synergism is unclear but it may be associated with the Onc activity in targeting microRNAs and/or NFkappaB and Cep activity also targeting NFkappaB. The data suggest that the combination of these two drugs, that individually express a low toxic profile, may have strong antitumor potential.
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PMID:Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines. 1844 30