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)

In order to get some insight into modifications of human papillomavirus (HPV) genomes which could play a role in tumor progression in epidermodysplasia verruciformis (EV), we studied three EV patients infected by HPV5 and one by HPV8, with cancers containing mostly or only episomal viral genomes with a deletion. The mutants were compared with the full-length genomes present in the benign lesions of each patient. Deletions affected the L1 and/or L2 open reading frames (ORFs), and extended in the 5' end of the long control region in two cancers. The isolates studied showed a polymorphism of restriction endonuclease cleavage sites and variations in the nucleotide sequence of the E6 ORF and the regions flanking the deletions. However, except for one patient infected by two distinct HPV5 variants, no difference was observed in the nucleotide sequence of isolates cloned from the benign lesions and the cancer of the same patient. This may suggest that point mutations are not involved in tumor progression. Comparison of nucleotide sequence data revealed an unexpectedly high number of nucleotide substitutions among the four HPV5 variants and the HPV8 variant, as compared with HPV5 and HPV8 published sequences. Changes involved 49 of the 457 nucleotides of HPV5 E6 ORF and 14 of the 465 nucleotides of HPV8 E6 ORF. This corresponds to amino acid substitutions affecting 17 of the 157 amino acids of HPV5 E6 proteins and 7 of the 155 amino acids of HPV8 E6 proteins. Half of the substitutions represent nonconservative changes. The variants showing the highest degree of sequence variation were detected in additional EV patients by PCR. This points to the existence of a set of HPV5 and HPV8 stable variants, encoding for multiple allelic forms of the transforming E6 gene.
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PMID:Genetic heterogeneity among human papillomaviruses (HPV) associated with epidermodysplasia verruciformis: evidence for multiple allelic forms of HPV5 and HPV8 E6 genes. 165 84

The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. Such a hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one and so on. A dissection of the pathway from a normal cell to a fully malignant tumor may thus be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. Similar mechanisms involving the distal short arm of chromosome 17 are apparent in astrocytic tumors and the events are shared by cells in each malignancy state. DNA sequencing indicates that these events accomplish the homozygosis of mutant alleles of the p53 gene. Copy number amplification of the epidermal growth factor receptor gene occurs in intermediate and late-stage tumors whereas loss of heterozygosity for loci on chromosome 10 is restricted to the ultimate stage, glioblastoma multiforme. These results suggest a genetic approach to defining degrees of tumor progression and the locations of genes involved in the pathway as a prelude to their molecular isolation and characterization.
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PMID:Molecular genetics of human cancer predisposition and progression. 201 Nov 37

The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. This hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one and so on. That is to say, a dissection of the pathway form a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events, we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. A similar mechanism involving the distal short arm of chromosome 17 is apparent in astrocytic tumors and the event is shared by cells in each malignancy stage. This is distinct from a loss of heterozygosity for loci on chromosome 10 which is restricted to the ultimate stage, glioblastoma multiforme. Further, this approach has has been extended to a wide variety of human cancers and shown to be generally applicable. The results suggest a genetic approach to defining degrees of tumor progression and a means for determining the genomic locations of genes involved in the pathway as a prelude to their molecular isolation and characterization. They have provided a molecular genetic-based oncology with clinical utility in differential pathology, in disease groupings for therapeutic purposes and in prenatal identification of latent disease carriers.
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PMID:Tumor progression stage: specific losses of heterozygosity. 248 36

The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. Such a hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one, and so on. That is to say a dissection of the pathway from a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events, we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. A similar mechanism involving the distal short arm of chromosome 17 is apparent in astrocytic tumors and the event is shared by cells in each malignancy stage. This is distinct from a loss of heterozygosity for loci on chromosome 10 which is restricted to the ultimate stage, glioblastoma multiforme. These results suggest a genetic approach to defining degrees of tumor progression and means for determining the genomic locations of genes involved in the pathway as a prelude to their molecular isolation and characterization.
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PMID:Mitotic abnormalities leading to cancer predisposition and progression. 255

Bursal lymphomas induced in chickens by avian leukosis viruses (ALVs) harbor proviral insertions that augment expression of an adjacent cellular oncogene, c-myc. To analyze such insertionally mutagenized c-myc genes in greater detail, we isolated molecular clones from two independent tumors. Precise proviral integration has occurred within the transcribed region of the c-myc gene in both mutant alleles. The proviruses bear different internal deletions that preclude the expression of the gag, pol, and env genes. The c-myc gene from bursal lymphoma LL4 contains a single copy of an ALV long terminal repeat (LTR), presumably the product of homologous recombination between LTRs at the ends of a normal provirus; the "solo" LTR is positioned in the correct orientation to act as a promoter for the c-myc gene. Bursal lymphoma LL3 contains an ALV provirus positioned upstream in the opposite transcriptional orientation to the coding exons of c-myc and deleted from a site within the leader region into the gag gene. In addition, the nucleotide sequence of the c-myc gene from tumor LL3 differs from the published sequence of the normal c-myc coding region at 3 positions of 180 determined. One of these changes, a silent nucleotide transition, is documented as a somatic mutation by restriction endonuclease mapping. It is flanked by two other candidate tumor-specific point mutations, one of which predicts an amino acid replacement, Pro----Thr at position 63. Thus, additional lesions that may affect the expression of viral genes and the quantity and nature of the putative c-myc gene product occur in provirally mutated c-myc alleles and may contribute to tumor progression.
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PMID:Proviral deletions and oncogene base-substitutions in insertionally mutagenized c-myc alleles may contribute to the progression of avian bursal tumors. 632 73

Although VL30 retrotransposable elements have been associated with certain cancers for nearly twenty years, because of their expression in rodent malignancies and recombination into murine sarcoma viruses, their causative role, if any, in cancer has been uncertain and enigmatic. Recent findings suggest loss of normal transcriptional control of specific VL30 element expression may make a critical contribution to tumor progression at a step associated with malignant conversion, by bringing into play a cellular program normally involved in wound healing. This program, the fibroblast anoxic response system, includes an adaptation to glycolytic metabolism, secretion of metalloproteinases, and activation of an endonuclease. While appropriate for facilitating debris removal during wound healing, loss of control of this program in a cell which has already progressed to the benign neoplastic state has the potential to simultaneously produce the invasiveness and genomic instability characteristic of malignancy. Examination of tumors and tumor derived cell lines has confirmed that key aspects of this system are in fact activated in cancer.
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PMID:Anoxia, wound healing, VL30 elements, and the molecular basis of malignant conversion. 839 Aug 32

An androgen receptor (AR) gene mutation identified in the androgen-dependent human prostate cancer xenograft, CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT for histidine to TAT for tyrosine and abolished a restriction site for the endonuclease SfaNI. SfaNI digestion of AR exon H DNA from normal but not from prostate cancer tissue indicated H874Y is a somatic mutation that occurred before the initial tumor transplant. CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in size to the AR mRNA in human benign prostatic hyperplasia. AR protein is present in cell nuclei by immunostaining as in other androgen-responsive tissues. Transcriptional activity of recombinant H874Y transiently expressed in CV1 cells in the presence of testosterone or dihydrotestosterone was similar to that of wild type AR. With dihydrotestosterone at a near physiological concentration (0.01 nM), H874Y and wild type AR induced 2-fold greater luciferase activity than did the LNCaP mutant AR T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100 nM) with H874Y stimulated a 3- to 8-fold greater response than with wild type AR and at 100 nM the response was similar with the LNCaP mutant. H874Y, like the LNCaP cell mutant, was more responsive to estradiol and progesterone than was wild type AR. The antiandrogen hydroxyflutamide (10 nM) had greater agonist activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR mutations that alter ligand specificity may influence tumor progression subsequent to androgen withdrawal by making the AR more responsive to adrenal androgens or antiandrogens.
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PMID:Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. 909 97

One of the "signature" phenotypes of highly malignant, poorly differentiated tumors, including hepatomas, is their remarkable propensity to utilize glucose at a much higher rate than normal cells, a property frequently dependent on the marked overexpression of type II hexokinase (HKII). As the expression of the gene for this enzyme is nearly silent in liver tissue, we tested the possibility that DNA methylation/demethylation events may be involved in its regulation. Initial studies employing methylation restriction endonuclease analysis provided evidence for differential methylation patterns for the HKII gene in normal hepatocytes and hepatoma cells, the latter represented by a highly glycolytic model cell line (AS-30D). Subsequently, sequencing following sodium bisulfite treatment revealed 18 methylated CpG sites within a CpG island (-350 to +781 bp) in the hepatocyte gene but none in that of the hepatoma. In addition, treatment of a hepatocyte cell line with the DNA methyltransferase inhibitors, 5'-azacytidine and 5'-aza-2'-deoxycytidine, activated basal expression levels of HKII mRNA and protein. Finally, stably transfecting the hepatocyte cell line with DNA demethylase also resulted in activating the basal expression levels of HKII mRNA and protein. These novel observations indicate that one of the initial events in activating the HKII gene during either transformation or tumor progression may reside at the epigenetic level.
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PMID:Glucose metabolism in cancer. Evidence that demethylation events play a role in activating type II hexokinase gene expression. 1256 45

Sister chromatid recombination (SCR) is a potentially error-free pathway for the repair of double-strand breaks arising during replication and is thought to be important for the prevention of genomic instability and cancer. Analysis of sister chromatid recombination at a molecular level has been limited by the difficulty of selecting specifically for these events. To overcome this, we have developed a novel "nested intron" reporter that allows the positive selection in mammalian cells of "long tract" gene conversion events arising between sister chromatids. We show that these events arise spontaneously in cycling cells and are strongly induced by a site-specific double-strand break (DSB) caused by the restriction endonuclease, I-SceI. Notably, some I-SceI-induced sister chromatid recombination events entailed multiple rounds of gene amplification within the reporter, with the generation of a concatemer of amplified gene segments. Thus, there is an intimate relationship between sister chromatid recombination control and certain types of gene amplification. Dysregulated sister chromatid recombination may contribute to cancer progression, in part, by promoting gene amplification.
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PMID:Molecular analysis of sister chromatid recombination in mammalian cells. 1559 Mar 23

The methylation level of 13 CpG-dinucleotides in the promoter region of the putative tumor suppressor gene RASSF1A (3p21.31) was analyzed in HPV-positive squamous cell carcinomas of cervix using methyl-sensitive restriction endonuclease analysis followed by PCR. The methylation from 3 to 13 CpG-dinucleotides was observed in 64% (25/39) tumors, 22% (2/9) morphologically normal tissues adjacent to tumors (P = 0.0306) and in 2 from 3 leucocytes of peripheral blood of patients. The methylation of these CpG-dinucleotides was absent in DNA of healthy donor leucocytes (0/10). Methylation level of the examined fragment of the RASSF1A promoter region was significantly higher in tumors of patients with lymph node metastases in comparison to tumors of patients without metastases (P = 8.5 x 10(-12)). The methylation frequency of RASSF1A gene was in two times higher than hemi- and homozygous deletion frequency at the region of location of this gene (chromosome 3p21.31), determined earlier. These data suggest that methylation of the RASSF1A gene is one of the main ways of this gene inactivation in HPV-positive cervical squamous cell carcinomas. The methylation of the RASSF1A gene is an early event in genesis of tumor and the level of methylation increased with tumor progression.
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PMID:[Methylation of the putative tumor suppressor gene, RASSF1A, in primary cervical tumors]. 1561 86


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