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)

During the past decade, remarkable progress has been made in our understanding of cancer-causing agents, mechanisms of cancer formation and the behavior of cancer cells. Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). It has been estimated that about 75-80% of all human cancers are environmentally induced, 30-40% of them by diet. Only a small minority, possibly no more than 2% of all cases, result purely from inherent genetic changes. Several lines of evidence confirm that the fundamental molecular event or events that cause a cell to become malignant occur at the level of the DNA and a variety of studies indicate that the critical molecular event in chemical carcinogenesis is the interaction of the chemical agent with DNA. The demonstration that DNA isolated from tumor cells can transfect normal cells and render them neoplastic provides direct proof that an alteration of the DNA is responsible for cancer. The transforming genes, or oncogenes, have been identified by restriction endonuclease mapping. One of the characteristics of tumor cells generated by transformation with viruses, chemicals, or radiation is their reduced requirement for serum growth factors. A critical significance of electrophilic metabolites of carcinogenes in chemical carcinogenesis has been demonstrated. A number of "proximate" and "ultimate" metabolites, especially those of aromatic amines, were described. The "ultimate" forms of carcinogens actually interact with cellular constituents to cause neoplastic transformation and are the final metabolic products in most pathways. Recent evidence indicates that free radical derivatives of chemical carcinogens may be produced both metabolically and nonenzymatically during their metabolism. Free radicals carry no charge but do possess a single unpaired electron, making the radical extremely reactive. That such forms may be important in the introduction of neoplastic transformation by chemicals from two lines of evidence. (1) Various molecules that inhibit the formation of free radicals, many of which are termed antioxidants, can inhibit the carcinogenic action of a variety of chemical carcinogens. (2) There are relatively specific metabolic reactions of certain chemical carcinogens, particularly of polycyclic hydrocarbons, for which it has been shown to proceed through free radical intermediates. In conclusion, free radical processes with direct effects on DNA can be proposed for a variety of human and animal carcinogens.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Free radicals in chemical carcinogenesis. 179 90

An unusually high incidence of interviral recombination was found in the process of integration of the polyomavirus genome concomitant with neoplastic transformation of nonpermissive cells. Transformants were isolated after mixed infections of Fischer rat cells with two mutants lacking restriction endonuclease sites and were analyzed for the presence of unselected integrated recombinant restriction fragments. A large fraction of the transformants isolated (38% of the 64 transformed cell lines studied) contained recombinant viral genomes that had undergone recombination in a 1.3-, 1.7-, or 3.6-kilobase-pair interval. More than 90% of these recombinant transformants showed evidence of crossovers in multiple intervals. To our knowledge, the recombination frequencies observed in these experiments represent the highest frequencies of homologous recombination reported for a mitotic mammalian system that does not involve transfection. In contrast to the elevated level of recombination in the integrated viral genomes, no evidence of recombination was obtained among the replicated unintegrated pool of viral genomes isolated from the same population of infected cells from which the recombinant transformants were derived. Either of two hypotheses can provide an explanation for the segregated recombination: either recombination occurs at elevated levels in a small, recombination-prone fraction of the population destined to become transformed, or recombination occurs only among those viral genomes which are engaged in the process of integration and thus interact with a recombinogenic host machinery (for example, the host scaffold). We favor the latter hypothesis.
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PMID:High-level recombination specific to polyomavirus genomes targeted to the integration-transformation pathway. 254 71

Hepatitis B virus (HBV) DNA was found to be integrated into seven sites in the DNA of the PLC/PRF/5 hepatoma cell line as determined by digestion with the restriction endonuclease HindIII which does not cut through the viral genome. The integration pattern was stable in the cell line, in tumours induced in athymic mice by this line and in cell lines derived from such tumours. Syntheses of hepatitis B surface antigen and alphafoetoprotein were maintained in the induced tumours and derived cell lines. A defective HBV DNA molecule (approx. 2.8 kilobase pairs) appears to be integrated in a head-to-tail tandem arrangement and it is proposed that such defective molecules may be involved in the process of neoplastic transformation by HBV.
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PMID:Defective hepatitis B virus DNA molecules detected in a stable integration pattern in a hepatoma cell line, and in induced tumours and derived cell lines. 619 51

The presence of hemoglobin H (beta 4), resulting from a deficiency of alpha-globin chain synthesis, was observed as an acquired characteristic in the red cells of five elderly patients with myeloproliferative disorders or preleukemia. The variability in amount of hemoglobin H and in the alpha/beta globin synthesis ratios in these patients is most likely explained by the relative proportions of normal and abnormal cell populations in the peripheral blood, since some reticulocyte fractions with balanced alpha/beta globin synthesis ratios and others with almost no detectable alpha-chain production could be obtained from these patients. In one patient, the hemoglobin H virtually disappeared despite continuing disease. The amount of cytoplasmic alpha-mRNA matched the proportion of alpha-chain synthesis and, in one patient, this was also true for nuclear RNA. However, extensive analysis of the alpha-globin gene complex by restriction endonuclease mapping revealed no detectable rearrangements of the normal gene organization in any of these patients, suggesting that transcription of each pair of alpha-globin genes on each chromosome 16 is defective. These observations have important implications for both the normal regulation of alpha-globin gene expression and the molecular basis of the underlying defect that is associated with the neoplastic transformation of these cells.
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PMID:Clinical features and molecular analysis of acquired hemoglobin H disease. 688 Nov 69

Arsenic is a known human carcinogen, but little evidence exists for its carcinogenicity in animals. In order to investigate the ability of inorganic arsenics to transform normal cells into a neoplastic state, mass cultures of normal, diploid Syrian hamster embryo (SHE) cells exposed to various concentrations of sodium arsenite or sodium arsenate for 48 hr were continually passaged and tested for neoplastic transformation, as determined by anchorage-independent growth in semisolid agar and tumorigenicity in newborn hamsters. Twenty-one of 22 (96%) untreated, control cultures senesced by 20 passages. While 1 culture escaped senescence, it did not acquire the ability to either grow in semisolid agar or form tumors in animals. Ten of 14 (71%) cultures exposed to sodium arsenite or sodium arsenate escaped senescence. Nine of the 10 (90%) arsenic-treated immortal cultures acquired the anchorage-independent phenotype. Five of 5 anchorage-independent cultures examined were tumorigenic. Two of 3 morphologically transformed colonies induced by sodium arsenate also acquired the ability to grow in semisolid agar when isolated. Amplification of the c-myc or c-Ha-ras oncogene was detected in 3 of 5 and 4 of 5 tumorigenic cell lines, respectively. Both c-myc and c-Ha-ras were amplified even in a preneoplastic, anchorage-dependent cell line, but neither was amplified in 6 of 9 anchorage-independent cell lines. Overexpression of c-myc and c-Ha-ras mRNA was observed in most of the neoplastically transformed cell lines but not in the preneoplastic cell line. Experiments using the methylation-sensitive restriction endonuclease isoschizomers HpaII and MspI revealed hypomethylation of c-myc and c-Ha-ras in the 5'-CCGG sequence of arsenic-exposed cell lines but not in the parental SHE cells or a spontaneously transformed cell line. Thus, inorganic arsenics induce neoplastic transformation of normal, diploid mammalian cells. Overexpression of oncogenes by DNA hypomethylation may participate in the arsenic-induced neoplastic transformation of mammalian cells.
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PMID:Transformation by inorganic arsenic compounds of normal Syrian hamster embryo cells into a neoplastic state in which they become anchorage-independent and cause tumors in newborn hamsters. 1211 94

The HMGA1 protein is a major factor in chromatin architecture and gene control. It plays a critical role in neoplastic transformation. In fact, blockage of HMGA1 synthesis prevents rat thyroid cell transformation by murine transforming retroviruses, and an adenovirus carrying the HMGA1 gene in the antisense orientation induces apoptotic cell death in anaplastic human thyroid carcinoma cell lines, but not in normal thyroid cells. Moreover, both in vitro and in vivo studies have established the oncogenic role of the HMGA1 gene. In this study, to define HMGA1 function in vivo, we examined the consequences of disrupting the Hmga1 gene in mice. Both heterozygous and homozygous mice for the Hmga1-null allele show cardiac hypertrophy due to the direct role of HMGA1 on cardiomyocytic cell growth regulation. These mice also developed hematologic malignancies, including B cell lymphoma and myeloid granuloerythroblastic leukemia. The B cell expansion and the increased expression of the RAG1/2 endonuclease, observed in HMGA1-knockout spleen tissues, might be responsible for the high rate of abnormal IgH rearrangements observed in these neoplasias. Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies.
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PMID:Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice. 3055 26

Altered DNA methylation has been linked to neoplastic cell transformation and is a hallmark of cancer progression. Therefore, the screening for differentially methylated sequences as tumor biomarkers has a significant implication in the clinical setting. To determine the cancer-linked alterations in DNA methylation pattern, we have applied an endonuclease, McrBC, to the existing methylation-sensitive arbitrarily primed polymerase chain reaction (msAP-PCR) method and developed McrBC-msAP-PCR. This modified approach allows detection of differentially methylated sites within unmethylated DNA domains enriched by regulatory sequences and CpG islands. In this method, we used digestion of DNA with the McrBC methylation-sensitive endonuclease to selectively exclude the methylated fraction of DNA, which comprises interspersed and tandem-repeated sequences and exons other than first exons, from analysis. The subsequent digestion of unmethylated DNA fragments with SmaI and HpaII methylation-sensitive restriction endonucleases followed by AP-PCR amplification resulted in the detection of unknown unique sequences associated with cancer-linked methylation changes in genomic DNA. Hypermethylation and hypomethylation are visualized by the increase or decrease in the band intensity of DNA fingerprints. By using this technique, we were able to differentiate clearly, identify, and characterize a number of novel unique DNA sequences with differentially methylated sites in normal and breast cancer cell lines and in normal and rat tumor liver tissues.
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PMID:Identification of differentially methylated sites within unmethylated DNA domains in normal and cancer cells. 1682 73

Oxidative DNA damage and DNA repair may mediate several cellular processes, like replication and transcription, mutagenesis and apoptosis and thus may be important for the organism development as well as its pathogenesis, including cancer. Activity of DNA repair enzymes can depend on many factors, such as gene polymorphism, mRNA and protein level, as well as enzymes activation and inhibition. Modulation of base excision repair pathway eliminating from DNA oxidatively formed lesions may be caused by the diet, inflammation and neoplastic transformation. Reactive oxygen species and some diet components induce transcription of several Base Excision Repair enzymes, e.g. major human AP-endonuclease, (APE1) and 8-oxoG-DNA glycosylase (OGG1). The carcinogenic process in human lung decreases repair activity for 8-oxoGin transcription independent manner, but increases repair activity of epsilon A and epsilon C, as measured in tumors and unchanged lung tissues of lung cancer patients. Thus, modulation of repair enzymes activities may be a cell response on their way to differentiation ot neoplastic transformation.
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PMID:Modulation of oxidative DNA damage repair by the diet, inflammation and neoplastic transformation. 1722 95