Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell growth and tumor progression. Previous work has shown that loss of functional TGF-beta type II receptor (RII) due to a frameshift mutation in the 5' half of the RII gene leads to TGF-beta resistance in a highly progressed, RER+ human colon carcinoma cell line designated HCT116. Expression of this mutated RII gene was highly repressed in RER+ cell lines such as HCT116 and RKO, as analyzed by RNase protection assays. Nuclear run-on and RII promoter-reporter (CAT) assays showed that the transcriptional levels of the RII gene in these RER+ cells were not reduced, compared to RII-expressing cells. However, the half-lives of the RII mRNA, as analyzed by RNase protection assays following actinomycin D treatment, were significantly decreased. This suggested that the decreased expression of the RII gene mutant was due to decreased mRNA stability. Furthermore, RII mRNA from HCT116 transfected with wild-type RII had a longer half-life than the endogenous mutated RII mRNA. A dominant negative RII mutant, which encodes a similarly truncated RII protein as HCT116 but lacks the extensive 3' untranslated region of RII mRNA, gave the same half-life as endogenous wild-type RII mRNA. We conclude that the frameshift mutation which results in a premature stop codon in the 5' half of the mRNA transcript accounts for the reduced RII mRNA levels in RER+ cells.
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PMID:Decreased Stability of Transforming Growth Factor beta Type II Receptor mRNA in RER+ Human Colon Carcinoma Cells 939 99

Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell growth and tumor progression. Previous work has shown that loss of functional TGF-beta type II receptor (RII) due to a frameshift mutation in the 5' half of the RII gene leads to TGF-beta resistance in a highly progressed, RER+ human colon carcinoma cell line designated HCT116. Expression of this mutated RII gene was highly repressed in RER+ cell lines such as HCT116 and RKO, as analyzed by RNase protection assays. Nuclear run-on and RII promoter-reporter (CAT) assays showed that the transcriptional levels of the RII gene in these RER+ cells were not reduced, compared to RII-expressing cells. However, the half-lives of the RII mRNA, as analyzed by RNase protection assays following actinomycin D treatment, were significantly decreased. This suggested that the decreased expression of the RII gene mutant was due to decreased mRNA stability. Furthermore, RII mRNA from HCT116 transfected with wild-type RII had a longer half-life than the endogenous mutated RII mRNA. A dominant negative RII mutant, which encodes a similarly truncated RII protein as HCT116 but lacks the extensive 3' untranslated region of RII mRNA, gave the same half-life as endogenous wild-type RII mRNA. We conclude that the frameshift mutation which results in a premature stop codon in the 5' half of the mRNA transcript accounts for the reduced RII mRNA levels in RER+ cells.
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PMID:Decreased stability of transforming growth factor beta type II receptor mRNA in RER+ human colon carcinoma cells. 940 53

A new sequence-specific RNase was isolated from human colon carcinoma T84 cells. The enzyme was purified to electrophoretical homogeneity by pH precipitation, HiTrapSP and Superdex 200 FPLC. The molecular weight of the new enzyme, which we have named RNase T84, is 19 kDa. RNase T84 is an endonuclease which generates 5'-phosphate-terminated products. The new RNase selectively cleaved the phosphodiester bonds at AU or GU steps at the 3' side of A or G and the 5' side of U. 5'AU3' or 5'GU3' is the minimal sequence required for T84 RNase activity, but the rate of cleavage depends on the sequence and/or structure context. Synthetic ribohomopolymers such as poly(A), poly(G), poly(U) and poly(C) were very poorly hydrolysed by T84 enzyme. In contrast, poly(I) and heteroribopolymers poly(A,U) and poly(A,G,U) were good substrates for the new RNase. The activity towards poly(I) was stronger in two colon carcinoma cell lines than in three other epithelial cell lines. Our results show that RNase T84 is a new sequence-specific enzyme whose gene is abundantly expressed in human colon carcinoma cell lines.
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PMID:New sequence-specific human ribonuclease: purification and properties. 970 18

Human dihydrodiol dehydrogenase (DD) isoforms are aldo-keto reductases (AKRs) that activate polycyclic aromatic hydrocarbons (PAHs) by oxidizing trans-dihydrodiol proximate carcinogens to reactive and redox-active ortho-quinones. Of these, human AKR1C1 (DD1) and AKR1C2 (DD2) oxidize trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to the cytotoxic and genotoxic metabolite benzo[a]pyrene-7,8-dione (BPQ) with the highest catalytic efficiency. Exposure of HepG2 cells to a panel of inducers revealed that mRNA encoding one or more human AKR1C member(s) was induced (3- to 10-fold) by benzo[a]pyrene and other polycyclic aromatic compounds (bi-functional inducers), electrophilic Michael acceptors and phenolic antioxidants (monofunctional inducers), and reactive oxygen species (ROS). The induction of AKR1C mRNA by bifunctional inducers was delayed with respect to the induction of CYP1A1 mRNA, and AKR1C mRNA was not induced by the nonmetabolizable aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These data suggest that, in contrast to the CYPs, induction of AKR1C member(s) by PAHs and other bifunctional inducers is mediated indirectly via an antioxidant response element rather than a xenobiotic response element. Immunoblot and enzymatic assays confirmed that the increases in AKR1C mRNA were faithfully translated into functional AKR1C protein(s). The increased DD activity in HepG2 lysates was inhibited only by high concentrations of ursodeoxycholate, which suggested that AKR1C2 (DD2, bile-acid-binding protein) was not the isoform induced. RNase protection assays identified AKR1C1 (DD1) mRNA as the transcript which was up-regulated by mono- and bi-functional inducers and ROS in both human hepatoma (HepG2) and colon carcinoma (HT29) cells. BPQ, the electrophilic and redox-cycling product of the AKR1C1 reaction, also induced AKR1C1 expression. Thus, BPQ formation by AKR1C1 results in both a chemical (redox-cycling) and a genetic (AKR1C1 induction) amplification of ROS in PAH-exposed cells. Because ROS have been implicated in both tumor initiation and tumor promotion, the amplification of ROS by this pathway may play a significant role in PAH carcinogenesis.
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PMID:Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase. 997 8

Peroxisomes and the activities of their enzymes have been reported to be significantly reduced in various types of tumors including the colon carcinoma. Therefore, the present study was designed to investigate the gene expression of several peroxisomal proteins in human colon carcinoma and additionally those of the peroxisome proliferator activated receptor alpha (PPARalpha) and PEX5, a receptor protein involved in the import of most peroxisomal matrix proteins. Samples from adenocarcinomas and adjacent normal colon were analyzed by immunohistochemistry and western blotting. The mRNA content was assessed by a novel sensitive dot blot RNase protection assay and northern blotting. By immunohistochemistry, peroxisomes were distinctly visualized in normal colonocytes but were not detected in colon carcinoma cells. The protein levels of catalase (CAT), acyl-CoA oxidase as well as the 22 and 70 kDa peroxisomal membrane proteins (PMP22 and PMP70) were all significantly decreased in carcinomas. The corresponding mRNAs for CAT and PMP70, however, were unchanged. In contrast, the mRNA of PEX5 was significantly increased. The expression of PPARalpha was not altered in tumors, neither at protein nor mRNA levels. These observations show that the reduction of peroxisomes and their proteins in colon carcinoma is not due to a generalized reduction of transcription of their genes. It seems more likely that this phenomenon is regulated at a post-transcriptional or translational level. Alternatively, and more likely, an impairment of the biogenesis of the organelle could account for the paucity of peroxisomes in colon carcinoma.
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PMID:Impairment of peroxisomal biogenesis in human colon carcinoma. 1035 77

Human inducible NO synthase (iNOS) expression is regulated by post-transcriptional mechanisms. The 3'-untranslated region (3'-UTR) of the human iNOS mRNA contains AU-rich elements (ARE), which are known to be important for the regulation of mRNA stability. The 3'-UTR of the human iNOS mRNA has been shown to regulate human iNOS mRNA expression post-transcriptionally. One RNA-binding protein known to interact with AREs and to regulate mRNA stability is the T cell intracellular antigen-1-related protein (TIAR). In RNA binding studies TIAR displayed high affinity binding to the human iNOS 3'-UTR sequence. In RNase protection experiments, the cytokine incubation needed for iNOS expression did not change TIAR expression in DLD-1 cells. However, overexpression of TIAR in human DLD-1 colon carcinoma cells resulted in enhanced cytokine-induced iNOS expression. In conclusion, TIAR seems to be involved in the post-transcriptional regulation of human iNOS expression.
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PMID:The RNA binding protein TIAR is involved in the regulation of human iNOS expression. 1619 98

Salmonella enterica serovar Enteritidis has emerged during the last 20 years as the major causative agent of food-borne gastroenteritis in humans and as the major infectious agent on poultry farms, replacing Salmonella enterica serovar Typhimurium as the dominant pathogenic serovar. Because adhesion to gut tissues and colonization of the alimentary tract, mediated in large part by the FimH adhesins located on type 1 fimbriae, is an important stage in the pathogenesis of both serovars, the binding properties of the FimH adhesins from these two enteropathogens were compared. Salmonella Enteritidis FimH protein and the Salmonella Typhimurium low-adhesive variant of this adhesin were expressed in Escherichia coli and the recombinant proteins were analysed for their ability to bind glycoproteins carrying different oligomannosidic structures and different types of eukaryotic cells. In static binding assays (ELISA and Western blotting) both FimH proteins bound equally well to all three tested glycoproteins (RNase B, horseradish peroxidase and mannan-BSA). In addition, no differences were found in the binding specificity of the FimH proteins and intact cells of Salmonella Enteritidis and Salmonella Typhimurium to human colon carcinoma or bladder cancer cells. The presence of the same amino acid residues at positions 61 (glycine) and 118 (phenylalanine) and the similar binding properties of these two adhesins suggest that the newly described FimH protein of Salmonella Enteritidis represents the low-adhesive variant found in Salmonella Typhimurium. To study the binding specificity of Salmonella Enteritidis FimH protein further, direct kinetic analysis using surface plasmon resonance was performed. With this method it was found that Salmonella Enteritidis FimH adhesin bound with the highest K(d) value to high-mannose type N-glycans carried by RNase B; about 100 times lower K(d) values were obtained in the interactions with mannan-BSA and horseradish peroxidase.
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PMID:Functional characterization of the FimH adhesin from Salmonella enterica serovar Enteritidis. 1662 51

Initiation of cell growth and neoplastic transformation frequently involves activation of growth factor receptor-coupled tyrosine kinases and stimulation of the phosphoinositide second messenger system. Altered expression of CD44 variants was reported in several malignant tumor types with possible implications for tumor progression and prognosis. CD44 variant expression was reported to be associated with second messenger activation and differentiation. We therefore investigated the effects of butyrate-induced short-term differentiation on phosphoinositide signaling, phospholipase C and protein kinase C activity and alteration of CD44 variant expression in human HT-29 colon carcinoma cells. HT-29 cells were cultured with sodium butyrate for 6 days. Phosphoinositide turnover was measured by [32P]orthophosphate incorporation and phospholipase C activity by determination of the release of [3H]inositolphosphates from [3H]myoinositol prelabeled cells. Protein kinase C activity was determined by histone III-S phosphorylation, PKC subtype expression by RNase protection analysis, and CD44 variant expression was determined by RT-PCR using variant-specific primers. Treatment of HT-29 human colon carcinoma cells with sodium butyrate caused a dose-dependent inhibition of cell proliferation (IC50, 2.5 mM) with morphologic signs of an enterocytic differentiation following 6 days of treatment. The phosphoinositide turnover as determined by 32P-incorporation under non-equilibrium conditions showed a 30-40% inhibition of labeled phosphoinositides and phosphatidic acid and a dose-dependent inhibition of cholinergically stimulated phospholipase C activity as a secondary event following butyrate-induced enterocytic differentiation. However, long-term incubation of HT-29 cells with phorbol ester or an inhibitor of classical and novel PKC subtypes did not affect cell proliferation. In butyrate-treated HT-29 cells activation of calcium-dependent protein kinase C by cholinergic stimulation or phorbolester treatment induced an increase in membrane-bound cPKC activity, while expression of distinct high- molecular CD44 variant transcripts v3 (670 bp), v5 (940 bp) and v8 (535 bp) were drastically reduced after butyrate pretreatment. Enterocytic differentiation of HT-29 colon carcinoma cells seems to be associated with alterations in phosphoinositide resynthesis, phospholipase C activity and ligand/receptor-induced PKC translocation. The observed reduction of distinct high-molecular CD44v3, v5 and v8 variants following butyrate-induced differentiation indicates an association of specific CD44 variant expression with the malignant phenotype of HT-29 colon cancer cells, thus being possible targets for new diagnostic and therapeutic strategies.
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PMID:Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells. 1936 Mar 23

Onconase, a ribonuclease isolated from Rana pipiens oocytes and early embryos, is a member of the RNase A superfamily. Onconase has anti-neoplastic properties both in vitro and in vivo, and is undergoing clinical evaluation. In the present study, Onconase was combined with or conjugated to MRK16, an anti-P-glycoprotein (Pgp) monoclonal antibody. The interaction of these combinations with vincristine (VCR) against parental and multidrug resistant (MDR), Pgp expressing, human colon carcinoma cells caused increased VCR cytotoxicity in vitro and enhanced survival of athymic nude mice given transplants of drug resistant HT-29(mdr1) cells in vivo. The results suggest that combination treatment with Onconase and other agents that modulate the chemosensitivity of Pgp-expressing human tumor cells has the potential to overcome MDR.
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PMID:Anti-tumor ribonuclease, combined with or conjugated to monoclonal antibody MRK16, overcomes multidrug resistance to vincristine in vitro and in vivo. 2154 69

fac-[Ru^II(CO)₃Cl₂(N³-Imidazole)] (Ru^IIIM), fac-[Ru^II(CO)₃Cl₂(N³-methyl-imidazole)] (Ru^IIMIM) and fac-[Ru^II(CO)₃Cl₂(N³-methyl-benzimidazole)] (Ru^IIMBI) are three ruthenium based CO releasing molecules (Ru-CORMs) that are cytotoxic towards ovarian and colon carcinoma cell lines. Detailed structural information on the adducts formed upon reaction of Ru^IIIM and Ru^IIMIM with hen egg white lysozyme and of the three Ru-CORMs with bovine pancreatic ribonuclease is provided here by X-ray crystallography. Comparative analysis of seven crystal structures of these adducts allows one to delineate some general trends in the reactivity of these Ru-CORMs with proteins. Indeed, in all cases Ru-CORMs bind these model systems upon detachment of the azole ligand and concomitant coordination to a protein His or Asp residue. Apparently the three Ru-CORMs progressively dissociate losing azoles, chlorides, and one or two CO molecules. Data were compared with those reported in the literature for adducts of the same proteins with other Ru-CORMs and with in-solution data previously obtained on the same systems. These results are potentially useful for a better understanding of the chemistry, potential toxicity and mechanism of actions of these interesting Ru-CORMs and are helpful in defining the molecular mechanisms of CO release.
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PMID:Ru-Based CO releasing molecules with azole ligands: interaction with proteins and the CO release mechanism disclosed by X-ray crystallography. 2870 64


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