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:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ten astrocytomas were tested for gene amplification or rearrangement utilizing distinct probes to nine different oncogenes by Southern hybridization. The probes spanned the four major protein-coding classes of oncogenes; growth factor proteins (csis); growth factor receptor/tyrosine kinase-related proteins [erbB1 (epidermal growth factor receptor, EGF-R), neu (HER2/neu, erbB2), mos, yes]; nuclear binding proteins (c-myc, c-fos); and guanosine 5'-triphosphate binding proteins (N-ras, H-ras). Three astrocytomas, all glioblastomas, showed amplification of EGF-R-related sequences, and two of these amplifications were rearranged. Both rearrangements appeared similar by two different restriction endonucleases. Our findings suggest that it is primarily the EGF-R protooncogene (erbB1) that is amplified or rearranged in astrocytic neoplasms. No other oncogenes were amplified or rearranged, although EGF-R and neu cross-hybridization produced a "pseudo-rearranged" pattern for neu in EGF-R-amplified cases. The similar EGF-R restriction endonuclease abnormalities seen in two patients warrant further study.
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PMID:Oncogene abnormalities in astrocytomas: EGF-R gene alone appears to be more frequently amplified and rearranged compared with other protooncogenes. 167 68

The RET proto-oncogene, a receptor tyrosine kinase, has been evaluated as a candidate gene for multiple endocrine neoplasia type 2A and type 2B (MEN 2A and MEN 2B), for familial medullary thyroid carcinoma (FMTC), and for sporadic cases of medullary thyroid carcinoma (MTC) and pheochromocytomas. We determined the genomic structure of RET and used single-strand conformational polymorphism (SSCP) analysis to identify sequence variants in genomic DNA from families segregating MEN 2 and FMTC. In addition, we examined paired tumour and lymphocyte genomic DNAs from individuals with sporadic cases of MTC and pheochromocytoma. Altogether, we and others found 21 missense mutations in five cysteines clustered in the extra-cellular domain of RET (exons 10 and 11) associated with 111 MEN 2A and FMTC families. In contrast, a single point mutation that results in the substitution of threonine for methionine within the catalytic core of the tyrosine kinase domain (codon 918, exon 16) is responsible for all 66 reported cases of MEN 2B. Two missense mutations and a six base-pair deletion were identified in MTC tumour DNA, but no mutations were identified from pheochromocytoma tumour DNAs. A predictive DNA test for MEN 2A-associated mutations in RET has been developed that is based on detection of missense mutations by polymerase chain reaction (PCR) amplification and restriction endonuclease cleavage. A dominant oncogene model for the action of the RET gene product is proposed as a mechanism of action in MEN 2A, MEN 2B, FMTC and for at least some cases of sporadic MTC.
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PMID:The RET proto-oncogene and cancer. 759 67

Although several tyrosine kinase-type growth factor receptors have been demonstrated in human colonic epithelial cells, the full spectrum of growth factor receptors has not been identified. Low stringency screening of a complementary DNA library prepared from the human colon cancer-derived cell line HT-29 with a probe containing the tyrosine kinase domain of human c-src kinase led to the identification and isolation of a clone containing a receptor class tyrosine kinase. This putative receptor was found to be identical to the human fibroblast growth factor receptor 3 (FGFR3) except for a region of 150 nucleotides (50 amino acids) encoding the presumptive ligand-binding domain, where it exhibited only 32% homology with the previously described FGFR3. The variant domain corresponded precisely to the splicing junctions of the exon encoding the carboxyl terminal half of the third immunoglobulin-like domain, suggesting that two forms of FGFR3 result from splicing of alternate exons in a manner similar to that previously found for FGFR1 and FGFR2. By prior convention, the previously reported from of FGFR3 was designated IIIc due to its high degree of homology with the IIIc domain of FGFR1 (83% homology) and the IIIc domain of FGFR2 (81% homology). However, the ligand-binding domain of FGFR3 found in the HT-29 cell line was more highly divergent from all previously reported FGFR immunoglobulin-like domain IIIs than any other two members of this receptor family. Therefore, we propose to designate the newly reported form as the FGFR3 IIIb variant. Genomic polymerase chain reaction confirmed that the IIIb-containing exon occupies a position 5' relative to the IIIc-containing exon within the FGFR3 gene. Northern blot analysis using a probe encompassing sequences unique to the FGFR3 IIIb mRNA confirmed the expression of a 4.4-kilobase transcript in two colon cancer-derived cell lines as well as normal human colonic mucosa. Using a technique combining reverse transcriptase polymerase chain reaction with restriction endonuclease digestion, cell lines, primary cells, and tissues were assessed for IIIb and IIIc transcripts; expression of the IIIb variant was associated with an epithelial lineage, while the IIIc variant was expressed predominantly in nonepithelial cells and tissues.
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PMID:Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. 792 41

The src-related protein tyrosine kinase p56lck is thought to be important in regulating maturation and functional responsiveness of T cells and thymocytes. In the present studies we report that expression of p56lck is suppressed during apoptosis. Using primary cultures of rat thymocytes, we found that agents that are effective in inducing apoptosis, including okadaic acid, dexamethasone, and antibodies to the CD3 receptor, also deplete cells of p56lck. This process is rapid, occurring within 24 h, and is not due to cytotoxicity. Inhibition of DNA fragmentation in apoptotic cells with the endonuclease inhibitor ZnCl2 failed to prevent depletion of p56lck, suggesting that it was not a consequence of the DNA degradation process. Using the thymic lymphoma cell line LSTRA, apoptosis was also associated with cellular depletion of p56lck. In contrast to thymocytes, this process required 48-72 h possibly because these cells overexpress p56lck. Although at this time we are uncertain as to the precise role of p56lck in the process of apoptosis, our results indicate that changes in the expression of this protein in thymocytes is an important marker of programmed cell death.
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PMID:Cellular depletion of p56lck during thymocyte apoptosis. 793 Sep 51

Negative selection of self-reactive immature T cells is mediated by TCR engagement and is thought to occur via apoptosis (programmed cell death). The requirement for the co-receptors CD4 and CD8 in negative selection has been demonstrated, but the biochemical mechanisms underlying their involvement in this process remain undefined. Here we present evidence that co-receptor engagement dramatically enhances CD3-induced endonuclease activation and cell death characteristic of apoptosis in immature thymocytes. The responses are associated with increased tyrosine phosphorylation of a number of cellular substrates, including the gamma isoform of phospholipase C, and with increased association of tyrosine phosphoproteins, including the protein tyrosine kinase p56lck, with the TCR complex. Co-receptor engagement also potentiated CD3-mediated Ca2+ increases via a mechanism dependent upon tyrosine kinase activation. Sustained Ca2+ availability was found to be necessary for endonuclease activation and apoptosis to occur. We suggest that CD4 and CD8 may participate in negative selection by enhancing TCR/CD3-induced tyrosine kinase activation and sustained Ca2+ increases that lead to endonuclease activation and apoptosis in self-reactive CD4+ CD8+ thymocytes.
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PMID:Co-receptor (CD4/CD8) engagement enhances CD3-induced apoptosis in thymocytes. Implications for negative selection. 807 59

The dominantly inherited Multiple Endocrine Neoplasia cancer syndrome type 2B (MEN2B) is characterized by the presence of medullary thyroid carcinoma (MTC), phaechromocytoma (PHAEO), mucosal neuromas, ganglioneuromas of the intestinal tract, skeletal and ophthalmic abnormalities. MEN2B has been associated with a specific point mutation in the tyrosine kinase domain of the RET proto-oncogene (918RET mutation). We investigated a Mexican patient MEN2B for the presence of the 918RET mutation using the polymerase chain reaction followed by restriction endonuclease digestion. We have detected this mutation in DNA from the patient's MTC, PHAEO, and peripheral blood cells, but not in DNA from the patient's mother, suggesting that this mutation arose de novo. Our results are in agreement with the suggestion that the 918RET mutation is present in a vast majority of MEN2B cases around the world.
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PMID:Presence of the 918 mutation in the RET proto-oncogene in a Mexican patient with multiple endocrine neoplasia type 2B. 970 May 74

The 2'-5'-oligoadenylate (2-5A) synthetases are a family of interferon-alpha (IFN-alpha) inducible enzymes that block viral replication by activating a latent endonuclease during viral infections. In Ramos cells, induction of mRNAs for the intermediate isoform of 2-5A synthetase (p69) requires five-fold higher IFN-alpha than is required for induction of the small isoform (p40). The p40 and p69 isoforms are similarly induced between 1 and 24 h with maximal induction at 8 h. At 48 h, however, p69 is more strongly induced than p40. Induction of p69 and p40 between 1 and 24 h is protein synthesis independent whereas at 48 h, p69 induction becomes dependent on protein synthesis. Initial induction of both isoforms requires tyrosine kinase activation and is enhanced by activation of a separate signalling pathway by the tumour promoter, 12-0-tetradecanoyl phorbol-13-acetate (TPA). These data suggest that induction of the p40 is predominantly protein synthesis independent, whereas p69 induction occurs in two phases, an initial protein synthesis independent phase and a delayed protein synthesis dependent phase.
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PMID:Protein synthesis-dependent and -independent induction of p69 2'-5'-oligoadenylate synthetase by interferon-alpha. 1052 12

3-Aminobenzamide (3AB) is an inhibitor of poly (ADP-ribose) polymerase (PARP), an enzyme implicated in the maintenance of genomic integrity, which is activated in response to radiation-induced DNA strand breaks. cDNA macroarray membranes containing 1536 clones were used to characterize the gene expression profiles displayed by mouse BALB/3T3 fibroblasts (A31 cell line) in response to ionizing irradiation alone or in combination with 3AB. A31 cells in exponential growth were pre-treated with 3AB 4mM 1h before gamma-irradiation (4Gy), remaining in culture during 6h until harvesting time. A31 cells treated with 3AB alone presented a down-regulation in genes involved in protein processing and cell cycle control, while an up-regulation of genes involved in apoptosis and related to DNA/RNA synthesis and repair was verified. A31 cells irradiated with 4Gy displayed 41 genes differentially expressed, being detected a down-regulation of genes involved in protein processing and apoptosis, and genes controlling the cell cycle. Concomitantly, another set of genes for protein processing and related to DNA/RNA synthesis and repair were found to be up-regulated. A positive or negative interaction effect between 3AB and radiation was verified for 29 known genes. While the combined treatment induced a synergistic effect on the expression of LCK proto-oncogene and several genes related to protein synthesis/processing, a negative interaction effect was found for the expression of genes related to cytoskeleton and extracellular matrix assembly (SATB1 and Anexin III), cell cycle control (tyrosine kinase), and genes participating in DNA/RNA synthesis and repair (RNA helicase, FLAP endonuclease-1, DNA-3 glycosylase methyladenine, splicing factor SC35 and Soh1). The present data open the possibility to investigate the direct participation of specific genes, or gene products acting in concert in the mechanism underlying the cell response to radiation-induced DNA damage under the influence of PARP inhibitor.
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PMID:Differential gene expression in gamma-irradiated BALB/3T3 fibroblasts under the influence of 3-aminobenzamide, an inhibitior of parp enzyme. 1237 59

PMR1 is an endonuclease that is activated by estrogen to degrade Xenopus albumin mRNA. A previous report showed that the functional unit of endonuclease-mediated mRNA decay is a approximately 680-kDa polysome-bound complex that contains both PMR1 and substrate mRNA. PMR1 contains two domains involved in endonuclease targeting to polysomes, an N-terminal domain that lies between residues 200 and 250, and a C-terminal domain that lies within the last 100 residues. Loss of either domain inactivated PMR1 targeting to polysomes and stabilized albumin mRNA. The current study identified a phosphorylated tyrosine residue within the C-terminal polysome-targeting domain and showed that this modification is required for PMR1-mediated mRNA decay. Changing this tyrosine to phenylalanine inactivated the targeting of PMR1 to polysomes, blocked binding of PMR1 to the functional complex containing its substrate mRNA, prevented the targeting of a green fluorescent protein fusion protein to this complex, and stabilized albumin mRNA to degradation by PMR1 in vivo. A general tyrosine kinase inhibitor inhibited the phosphorylation of PMR1, which in turn inhibited PMR1-catalyzed degradation of albumin mRNA. These results indicate that one or more tyrosine kinases functions as a regulator of endonuclease-mediated mRNA decay.
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PMID:Endonuclease-mediated mRNA decay requires tyrosine phosphorylation of polysomal ribonuclease 1 (PMR1) for the targeting and degradation of polyribosome-bound substrate mRNA. 1537 58

The mRNA endonuclease PMR1 initiates mRNA decay by forming a selective complex with its translating substrate mRNA. Previous work showed that the ability of PMR1 to target to polysomes and activate decay depends on the phosphorylation of a tyrosine residue at position 650. The current study shows that c-Src is responsible for activating this mRNA decay pathway. c-Src was recovered with immunoprecipitated PMR1, and it phosphorylates PMR1 in vitro and in vivo. The interaction with c-Src involves two domains of PMR1: Y650 and a series of proline-rich SH3 peptides in the N terminus. In cells with little c-Src, PMR1 targeting to polysomes is induced by constitutively active c-Src but not by inactive forms of the kinase. Similarly, only active c-Src induces PMR1-mediated mRNA decay. Finally, we show that EGF rapidly induces c-Src phosphorylation of PMR1, providing a direct link between tyrosine kinase-mediated signal transduction and mRNA decay.
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PMID:c-Src activates endonuclease-mediated mRNA decay. 1734 62


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