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)

Activation of an endogenous endonuclease has been observed in conjunction with the structural changes of apoptosis in a wide variety of cell types and circumstances. The endonuclease is present constitutively in some cells (e.g. rodent cortical thymocytes) in which apoptosis is readily triggered by many unrelated stimuli, but is inducible in others. Purification of this enzyme is an objective of some importance in apoptosis research, as it might act as a marker of susceptibility to apoptosis and lead to better understanding of the regulation of the process as a whole. Early data suggest that the thymocyte endonuclease is an anionic protein of molecular weight greater than 110 kDa, with a pH optimum of 7.5 and a double-strand cleavage preference. Its activity, and the induction of apoptosis as a whole, is regulated by several familiar cellular proto-oncogenes and oncosuppressor genes, including c-myc, Ha-ras, bcl-2 and p53.
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PMID:The apoptosis endonuclease and its regulation. 133 78

The human p53 gene, a putative tumor suppressor gene, has a polymorphism in amino acid residue 72. We recently developed a method of detecting codon 72 polymorphism in this gene by digestion of polymerase chain reaction-amplified DNA using an allele-specific restriction endonuclease. This polymorphism allows the identification of loss of heterozygosity for the coding region of the p53 gene in limited tissue samples in a short time without using radioactive materials. We examined 33 patients with renal cell carcinoma and 29 with bladder cancer; heterozygosity in the p53 gene was lost in 60% (6 of 10 cases) and 73% (8 of 11 cases) of the renal and bladder tumors, respectively. Additionally, the assay's sensitivity could be improved by using DNA extracted from frozen sections of the tumors. Because the proportions of tumor cells and nontumor cells could be assessed by microscopic evaluation of the frozen sections, we were able to minimize contamination from nontumor cells, which occasionally causes false readings of retained heterozygosity. This simple and sensitive method for detecting loss of heterozygosity in the p53 gene makes it possible to rapidly screen a large number of tissue samples and has the potential to be a useful diagnostic tool for a wide variety of human neoplasms.
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PMID:Detection of loss of heterozygosity in the p53 gene in renal cell carcinoma and bladder cancer using the polymerase chain reaction. 200 30

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

Allelic deletions of the p53 gene previously were demonstrated by Southern hybridization to occur in high frequency in sporadic colon carcinomas and in a variety of other human tumors. We have examined the frequency of allelic loss of the p53 gene in carcinoma and dysplasia arising in patients with chronic ulcerative colitis who are heterozygous for the codon 72 polymorphism in exon 4 of the p53 gene. Cells derived from carcinoma and dysplasia specimens from 10 patients who were heterozygous at this locus were sorted by flow cytometry on the basis of DNA content. The p53 exon 4 region was amplified from diploid and aneuploid populations, via a polymerase chain reaction (PCR), and digested with BstUI. Three of three carcinomas, four of six dysplasias, and one patient who was indefinite for dysplasia demonstrated evidence of allelic loss of the p53 gene. Seven of ten cases of sporadic colon carcinoma, analyzed for comparative purposes, exhibited loss of a p53 allele. These results demonstrate that PCR analysis, followed by restriction endonuclease digestion of a polymorphic locus, can provide a rapid, definitive method for analyzing loss of heterozygosity in small numbers of cells from colonic mucosa. Such loss precedes cancer in ulcerative colitis and can be present in its earliest histologically identifiable precursor.
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PMID:Frequent loss of a p53 allele in carcinomas and their precursors in ulcerative colitis. 204 25

The present studies were initiated to define the coding region of a 34 kilodalton (kd) protein (p34) frequently observed with antibodies from HTLV-III/LAV-infected people by immunoblotting and radioimmunoprecipitation (RIP) techniques. We have directly mapped this viral protein to the pol gene of HTLV-III/LAV by radiolabeled amino acid sequence analysis. This region at the 3' end of the pol gene is predicted to encode the endonuclease/integrase of the virus. The seroprevalence rate of antibodies to the pol gene products p64 and p53 and to the endonuclease p34 were evaluated. Of 161 HTLV-III/LAV seropositive people tested by immunoblotting procedures, greater than 98% had antibodies which reacted to p64/p53 and 92.6% reacted to p34 indicating that these viral proteins are highly immunogenic in nature. We have also analyzed the serum of nine healthy people living in West Africa who were infected with HTLV-IV, a closely related retrovirus. Nine of nine seropositive people had antibodies that cross-reacted to p34 of HTLV-III/LAV, whereas only seven of nine reacted to p64/p53. These studies and our earlier observations indicate that current diagnostic procedures for screening for HTLV-III/LAV infection may also detect HTLV-IV seropositive individuals, pointing to a need for more specific assay systems.
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PMID:Immunogenic nature of a Pol gene product of HTLV-III/LAV. 302 60

Serum samples from 27 patients infected with human T-cell lymphotropic virus type III (14 with acquired immune deficiency syndrome [AIDS] and 13 with AIDS-related complex) were examined for antibodies to viral proteins by the Western blot method and with four different commercial solid-phase enzyme-linked immunosorbent assays (ELISAs). Virus-specific bands on blots at molecular masses of 64, 55, 53, 41, 31, 24, and 17 kilodaltons were observed. Rank correlation matrices were calculated to relate the intensity of viral bands, stage of illness, and ELISA kit optical densities (ODs). Groups of bands tended to covary in intensity: p17, p24, and p55 (gag gene products); p53 and p64 (pol gene products); and p31 (pol/endonuclease gene product) and p41 (env gene product). Blots of sera from AIDS-related complex patients usually showed strong activity against all viral proteins, while those of sera from AIDS patients characteristically showed strong reactivity only at the pol/endonuclease and env bands. For one ELISA kit (Abbott Laboratories, North Chicago, Ill.), ODs correlated well with the env and pol band intensity scores, while ELISA ODs with other kits (from Litton Industries, Sunnyvale, Calif.; Electro-Nucleonics, Inc., Fairfield, N.J.; and E.I. du Pont de Nemours & Co., Inc., Wilmington, Del.) correlated closely with gag band intensity scores. We conclude that human T-cell lymphotropic virus type III Western blot patterns are determined by (i) viral protein processing pathways and (ii) the stage of illness of the patient and may reflect (iii) the ELISA method used for serum screening.
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PMID:Variations in Western blot banding patterns of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus. 354 2

A cDNA transcript of Rous sarcoma virus, which contained the long terminal repeat (LTR) and some additional 3'-terminal sequences, was inserted into the plasmid pBR322. This recombinant plasmid, p53, was then used as a hybridization probe to detect viral terminal sequences in DNA from a number of tissues of birds with a variety of avian leukosis virus (ALV)-induced proliferative diseases. Using restriction endonuclease digestion and blot hybridization analysis, we detected, in addition to standard ALV genomes, viral terminal sequences linked to host DNA and not to viral genes. In DNA from bursal lymphomas and nephroblastomas, we observed small numbers of integration sites occupied by sequences in p53 and lacking most or all of the remainder of the viral genome. In DNA from osteopetrosis, we observed apparently multiple copies of molecules containing host DNA linked to viral LTR sequences. Some of these structures were contained in discrete, probably unintegrated, DNA molecules. We concluded that viral LTR sequences can be inserted as independent elements during recombination with host DNA in some forms of interaction between exogenous retroviruses and host cells. Because the LTRs have been implicated in integration and transcription of viral genes, the possibility that translocation or activation, or both, of host genes may occur as a consequence of viral infection is reinforced by these observations.
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PMID:Independent recombination between avian leukosis virus terminal sequences and host DNA in virus-induced proliferative disease. 626 28

Size separation after UV-endonuclease digestion of DNA from UV-irradiated human cells using denaturing conditions fractionates the genome based on cyclobutane pyrimidine dimer content. We have examined the largest molecules available (50-80 kb; about 5% of the DNA) after fractionation and those of average size (5-15 kb) for content of some specific genes. We find that the largest molecules are not a representative sampling of the genome. Three contiguous genes located in a G+C-rich isochore (tyrosine hydroxylase, insulin, insulin-like growth factor II) have concentrations two to three times greater in the largest molecules. This shows that this genomic region has fewer pyrimidine dimers than most other genomic regions. In contrast, the beta-actin genomic region, which has a similar G+C content, has an equal concentration in both fractions as do the p53 and beta-globin genomic regions, which are A+T-rich. These data show that DNA damage in the form of cyclobutane pyrimidine dimers occurs with different probabilities in specific isochores. Part of the reason may be the relative G+C content, but other factors must play a significant role. We also report that the transcriptionally inactive insulin region is repaired at the genome-overall rate in normal cells and is not repaired in xeroderma pigmentosum complementation group C cells.
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PMID:Identification of a large genomic region in UV-irradiated human cells which has fewer cyclobutane pyrimidine dimers than most genomic regions. 748 Jan 36

2-chloroadenosine induced DNA fragmentation and cell death in human thymocytes primarily by Ca(2+)-dependent mechanisms. Incubation of human thymocytes with 2-chlorodeoxyadenosine (5-1000 nM) also induced cell death (apoptosis) which was dependent on macromolecule synthesis and involved activation of an endonuclease which was inhibited by Zn2+. The effect of 2-chlorodeoxyadenosine was prevented by addition of dipyridamole, a strong nucleoside transport inhibitor, or of deoxycytidine, previously shown to compete for uptake by deoxycytidine kinase. 2-Chlorodeoxyadenosine-induced apoptosis did not involve increases in the cytosolic Ca2+ concentration, but required the presence of intracellular Ca2+. It was not inhibited by activators of protein kinase C previously shown to inhibit Ca(2+)-dependent cell death. Addition of 2-chlorodeoxyadenosine induced an increase in the amount of p53 in human thymocytes, while 2-chloroadenosine had no effect. These data suggest that 2-chloroadenosine and 2-chlorodeoxyadenosine induce cell death in human thymocytes via different signalling pathways.
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PMID:The 2-chlorodeoxyadenosine-induced cell death signalling pathway in human thymocytes is different from that induced by 2-chloroadenosine. 748 99

In most cases somatic mutations in disease-related genes do not give rise to a functional change of the mutated cell which would allow its isolation or expansion in vitro. Therefore, selection of mutated cells on the basis of an altered phenotype has to be replaced by biochemical separation and detection of the altered sequence of the gene of interest. In the RFLP/PCR (RFLP, restriction fragment length polymorphism) approach of 'genotypic' mutation analysis base pair changes, small deletions and insertions are measured which are located in a restriction enzyme recognition sequence and render this site resistant to cleavage by the corresponding endonuclease. The resistant DNA sequence containing the mutated site is amplified by PCR only after wild-type DNA has been eliminated by restriction digestion. Amplified DNA is directly sequenced or cloned into lambda gt10 and mutants are quantitated by oligonucleotide plaque hybridization. Absolute mutation frequencies are estimated relative to an internal 'mutant standard'. The RFLP/PCR protocol has been developed with mixtures of plasmid constructs containing wild-type inserts of the human c-H-ras1 protooncogene or inserts with base pair changes in an MspI site, a PvuII site and a TaqI site of this gene. As few as 1-5 mutated copies could be rescued from 10(7)-10(9) copies of the corresponding wild-type sequence. The RFLP/PCR protocol was successfully applied to the determination of N-ethyl-N-nitrosourea-induced mutations in codon 12 of c-H-ras1 (MspI site 1695-1698) and codon 248 of the p53 tumor suppressor gene (MspI site 14067-14070) in human skin fibroblasts. The RFLP/PCR approach holds promise for molecular toxicology and epidemiology.
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PMID:Genotypic mutation analysis by RFLP/PCR. 768 55


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