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At least 523 records · Page 29Linked to original sources
PubMed1988

Structure of the yeast HOM3 gene which encodes aspartokinase.

The yeast HOM3 gene has been cloned molecularly by complementation of a HOM3 mutant. The gene is located about 8 kilobase pairs from HIS1 and is present as a single copy in the yeast genome. Mutations in HOM3 result in a requirement for threonine and methionine (or homoserine) for growth and a lack of detectable aspartokinase activity. The nucleotide sequence of HOM3 predicts an enzyme 414 amino acids long that shows homology to the three Escherichia coli aspartokinases, indicating that it is the structural gene for yeast aspartokinase. An approximately 1800-base pair mRNA is transcribed from the HOM3 gene, initiating at several start sites, 80 and 70 base pairs downstream, respectively, from two TATA boxes. Upstream of the TATA boxes is a single TGACTC sequence. This sequence has been shown to be essential for regulation of several genes that encode amino acid biosynthetic enzymes by the general control system. However, no increase in aspartokinase mRNA is observed under general control derepressing conditions.

Amino Acid Sequence↗
PubMed1979

[Change in the karyotypic structure of mouse and rat rhabdomyosarcomas on their transplantation into the anterior chamber of the eye].

A study has been made of 7 transplatable lines of mice rhabdomyosarcomas and one line of rat rhabdomyosarcoma during their transplantation into the eye anterior chamber subcutaneous tissue. In all, 10 subcutaneous transplants and 15 transplants into the eye anterior chamber (EAC) were examined. Etanol fixed print smears were subjected to the Feulgen reaction to measure the DNA content using a cytophotometer MCPhU-1; 100 cells being measured in each transplant. In the majority of the EAC transplants, a statistically significant decrease of the karyotypic variability was found in additionto the augmentation to the diploid cell ratio as compared to subcutaneously proliferating populations of the same tumour lines. In some cases EAC transplants displayed exclusively diploid (periploid) populations of tumour myoblasts. Shifts in the karyotypic structure of populations towards diploidy, revealed during the cultivation of transplantable rhabdomyosarcomas, may be regarded as a phenomenon of the "karyotypical normalization" of tumour cells. The disappearance or sharp decrease of tetraploid or hypertetraploid classes of cells in EAC transplants may be due to the increase of their selective value in condition of immunological privilege of diploid, karyotypically normal cells, and of reduction of the genome mutation frequency in a diploid fraction of tumor myoblast populations.

Animals↗
PubMed1983

[Manifestation of malignancy in somatic hybrids obtained by the cell fusion of 2 tumor lines].

Malignancy of 6 independent hybrid clones derived from fusion of two tumor cell lines of Djungarian hamster, which had been transformed with SV40 virus, was studied. In most of the hybrid clones, suppression of the ability to grow progressively in vivo and the increase in the latent period of tumor occurrence were observed. These data bear witness to suggestion about the existence of different genetic alterations in these tumor cells. Suppression of malignancy does not depend on the genome mutations leading to cell polyploidization, since no decrease in tumorigenicity was found in polyploid cell clones of the high tumor cell line. These polyploid cells can actively form colonies in the soft agar medium.

Animals↗
PubMedDate not supplied

[Incidence of chromosome aberrations in the bone marrow of monkeys and their progeny after exposure to aflatoxin B1].

A mutagenic effect of aflatoxin B1 (AFB1) was studied in somatic cells of primates. It is shown that AFB1 elevates the chromosome aberration frequency in bone marrow cells of two monkey species: Macaca mulatta and Papio hamadryas. Genome mutations were found in these experimental primates simultaneously with chromosome aberrations. The AFB1-induced chromosome aberrations were revealed at least during two years of the study. The fact of the chromosome aberration frequency increase was established in Macaca babies born from females who received AFB1 in pregnancy.

Aflatoxin B1↗
PubMed1980

[Cytophotometric study of the progeny of clonogenic mouse rhabdomyosarcoma cells in lung tissue].

50 clones of murine rhabdomyosarcoma were grown in lungs, DNA contents of interphase nuclei of these clones being measured cytophotometrically. Significant differences in the mean DNA contents of clones obtained were observed, reflecting karyotypic differences of the initial clonogenic cells. The progenies of clonogenic cells had very high genome mutation rates (17.4 +/- 0.3.10(-2), and cells with increased numbers of chromosomes arose more frequently than hypoploid cells (12.5 +/- 0.3 and 2.9 +/- 0.2.10(-2), respectively). The mutability of tumor cells was non-equal in different clones, and positive correlations were observed between the mean DNA contents and mutability of the clones, whereas negative correlations were noticed between mutability and rates of cell proliferations.

Animals↗
PubMed1981

[Variability in the DNA content in the progeny of the clonogenic cells from transplantable rat rhabdomyosarcoma].

Transplantable rat rhabdomyosarcoma RA-2 selected for affinity to lung tissue was cloned in vivo, and DNA contents of interphase nuclei was cytophotometrically measured in progenies of 121 clonogenic cells implanted in the lungs. Clone populations have shown a high karyotypic heterogeneity, karyotypic structure being unchanged from the 16th to the 28th selection cycles investigated. Karyotypic heterogeneity is reproduced due to the high rate of genome mutations in the progenies of clonogenic cells (11.10-2-14.10-2 per cell per generation). Cells with increased numbers of chromosomes arose 3 fold more frequently than cells with decreased chromosome numbers, tumor cell mutability being non-equal in different clones.

Animals↗
PubMed1994

Abnormalities of p53 protein expression in cutaneous disorders.

Abnormalities in the p53 gene and in expression of its protein product are among the most frequent changes demonstrated in a variety of human cancers. p53 Is a nuclear phosphoprotein that in the natural form or "wild-type" can bind to DNA and prevent cells from entering into the S phase of the cell cycle. There is an increase in wild-type p53 after exposure of the skin to UV light, which allows for DNA repair before replication that would make DNA damage permanent. A loss of this protective influence destabilizes the genome. Mutation of the p53 gene commonly causes a defective protein that is degraded more slowly and accumulates in the cell to the extent that it becomes detectable by routine immunocytochemistry. These abnormalities precede the development of cancer in some examples. Studies of precursor lesions have used mainly immunohistochemical techniques that show p53 protein overexpression. The relationship between such overexpression and actual mutation of the p53 gene is controversial because overexpression of "wild-type" p53 protein also can occur. Mutations in the p53 gene have been observed in many actinic keratoses, basal cell carcinomas, and squamous cell carcinomas, and in a small proportion of malignant melanomas. Specific types of pyrimidine transitions have pointed to a role for UV light in these mutations. Molecular analysis is needed to determine whether or not immunocytochemical staining is truly reflective of mutation or is due to some other mechanism that causes an increased expression of wild-type p53.

Gene Expression↗
PubMed1993

Hepatitis B today: clinical and diagnostic overview.

The hepatitis B virus is a member of an unusual family of noncytopathogenic, hepatotropic DNA viruses--the hepadnaviruses. The complete virus comprises a lipoprotein coat, the hepatitis B surface antigen, enveloping a nucleocapsid core that contains a small, circular DNA molecule. Four open reading frames have been identified on the hepatitis B virus DNA genome. They encode seven proteins, including a hepatitis B virus DNA polymerase molecule with reverse transcriptase activity. The replication of the virus resembles that of retroviruses and occurs predominantly but not exclusively in hepatocytes. Virus variants involving genomic mutations have been identified. Testing for hepatitis B surface antigen permits detection of many but not all acutely infected patients. Diagnosis of acute infection rests on the identification of IgM antibodies to the hepatitis B core antigen. Antibody to hepatitis B surface antigen appears in serum during the convalescent phase of hepatitis B virus infection. It is the neutralizing, protective antibody largely responsible for immunity to reinfection. In persistent infection hepatitis B surface antigen is present, antibody to hepatitis B core antigen is predominantly an IgG antibody, antibody to hepatitis B surface antigen is not detectable or is present in very low titers and viral replication may be active. Persistent infection leads to an asymptomatic carrier state, chronic hepatitis, cirrhosis and hepatocellular carcinoma. No specific treatment exists for acute hepatitis B virus infection. Current data indicate that approximately 50% of adults who have chronic infection achieve virologic, biochemical and histologic remission from treatment with alpha-2b-interferon.

Hepatitis B↗
PubMed1996

Hepatoma-derived integrated HBV DNA causes multi-stage transformation in vitro.

The hepatoma-derived hepatitis B virus (HBV) DNA insert HU-a has recently been shown to contain two viral transactivator genes, X and preS2 /S. We report here that HU-a induces malignant transformation after stable transfection of the fetal mouse hepatocyte line FMH202, as indicated by soft agar growth and nude mouse tumorigenicity. Transfections with HU-a subclones, containing the X gene of the preS2 /S gene alone or sequences without transactivator gene, respectively, suggested that the X gene is essential for transformation. Sequential stages of transformation and tumor progression were analysed by injection of the stably transfected FMH202 lines into nude mice, explanation of the resulting tumors and re-establishment of cell lines from the tumors. Comparison of two HU-a-transformed cell lines by HBV mRNA hybridization, Southern analysis and chromosomal in situ hybridization revealed that integrated HBV DNAs were involved in major chromosomal rearrangements in both cases. Interestingly, recombination of the HBV Dna insert during the nude mouse passage had completely abolished HBV-specific transcription in one case, indicating that expression of integrated HBV genes, while presumably involved in early transformation, is dispensable at later stages of tumor progression. The sequential transformation observed in this experimental system suggests that expression of the X gene by integrated viral DNA and subsequent hepatocyte genome mutations might both contribute to HBV-associated liver carcinogenesis.

Animals↗
PubMedDate not supplied

[The specific serological profile in hepatitis B virus infection in children].

UNLABELLED: Hepatitis B virus infection (HBV) has a very well known specific serologic profile. In the last years the molecular biology methods reveal some "particular serological profiles" by genomic mutation. One particular profile consists in the absence of anti-HBc total antibodies simultaneously with the presence of HBsAg. Our tested group consists of 372 children aged 0.1 to 15 years. The presence of HBsAg was determined by ELISA "sandwich" and confirmed by neutralisation test. For HIV infection we used two ELISA tests (competitive and indirect) and the Western Blot test for confirmation. Of the total, there were 13 children HBsAg positive and without anti-HBc antibody (3.49% respectively), 7 of the 13 children (53.8%) were dystrophic and 4 were HIV positive (30.76%). From 372 cases, 104 were HBsAg positive (27.9%) and 53 (14.2%) of them had chronic hepatitis. CONCLUSIONS: 1. The particular serologic profile requires the testing of all serological markers specific for HBV. 2. This particular serologic profile is correlated with HIV positive status and dystrophy.

Adolescent↗
PubMed1997

Age-related negative associations between parameters of cytogenetic damage and ex vivo (+/-)-anti-benzo(a)pyrene diolepoxide-induced unscheduled DNA synthesis in smoking humans.

Chemical or physical modification of DNA may cause an increase in genomic mutations or other genetic alterations, which may ultimately result in the onset of cancer. To avoid these deleterious effects of DNA damage, humans possess DNA repair mechanisms. Decreased DNA repair, induced ex vivo by UV light or ionizing radiation in human peripheral blood lymphocytes (PBLs), has been associated with aging. The aim of this study was to investigate whether repair of DNA damage, after ex vivo exposure of PBLs obtained from smokers (n = 20) to (+/-)-anti-benzo(a)pyrene diolepoxide [(+/-)-anti-BPDE], which is a mixture of reactive metabolites from the environmental carcinogen benzo(a)pyrene, is also associated with age. Furthermore, age-related associations between ex vivo (+/-)-anti-BPDE-induced DNA repair and the frequency of endogenous cytogenetic damage (sister chromatid exchange frequencies and micronuclei frequencies) in PBLs were evaluated. A statistically significant negative association was observed between ex vivo (+/-)-anti-BPDE-induced unscheduled DNA synthesis and age of the donors. Also, parameters of endogenous lymphocytic cytogenetic damage were negatively associated with ex vivo (+/-)-anti-BPDE-induced unscheduled DNA synthesis and positively associated with age in this population. It is concluded that, with increasing age, a decrease in lymphocytic excision repair capacity may be responsible for increased lymphocytic DNA damage in smokers.

Adult↗
PubMedDate not supplied

[The dynamics of the cytogenetic effects in the peripheral blood lymphocytes of those who worked in the cleanup of the aftermath of the accident at Chernobyl Atomic Electric Power Station].

Dynamics of cytogenetic anomalies in liquidators of the Chernobyl accident has been studied. Dicentric and ring frequencies appeared to be the most informative criteria of radio-induced chromosome aberrations. The rate of cell elimination with dicentrics and rings was higher in liquidators exposed to more than 25 cGy of radiation that in those exposed to less than 25 cGy of radiation. The rate of elimination of chromatid-type aberrations and genomic mutations was very low in the group of liquidators exposed to higher dose of radiation.

Cells, Cultured↗
PubMed2006

Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability.

Mutations in genes coding for succinate dehydrogenase (SDH) subunits are believed to contribute to cancer and aging, but the mechanism for this is unclear. Hamster fibroblasts expressing a mutation in SDH subunit C (SDHC; B9) showed 3-fold increases in dihydroethidine and dichlorodihydrofluorescein (CDCFH(2)) oxidation indicative of increased steady-state levels of O2(.-) and H2O2, increases in glutathione/glutathione disulfide (indicative of oxidative stress), as well as increases in superoxide dismutase activity, relative to parental B1 cells. B9 cells also showed characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation-induced cytotoxicity. Expression of wild-type (WT) human SDHC in B9 cells caused prooxidant production, glucose consumption, sensitivity to glucose deprivation-induced cytotoxicity, and aneuploidy to revert to the WT phenotype. These data show that SDHC mutations cause increased O2(.-) production, metabolic oxidative stress, and genomic instability and that mutations in genes coding for mitochondrial electron transport chain proteins can contribute to phenotypic changes associated with cancer cells. These results also allow for the speculation that DNA damage to genes coding for electron transport chain proteins could result in a "mutator phenotype" by increasing steady-state levels of O2(.-) and H2O2.

Animals↗
PubMed1995

Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons.

Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This statement is supported by the observations that the classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and that a significant number of FBN1 mutations have been identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FBN1. On completion for a panel of nine probands with classic MFS, six new mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characterized in the early stages of a larger screening project. These 15 mutations were equally distributed throughout the gene and, with one exception, were specific to single families. One-third of mutations created premature termination codons, and 6 of 15 substituted residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. Mutations causing severe and rapidly progressive disease that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to this phenotype.

Base Sequence↗
PubMed1998

Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome.

To elucidate the role of the KVLQT1 gene in the pathogenesis of long QT syndrome (LQTS), we have established a screening system for detecting KVLQT1 mutations by the polymerase chain reaction-single strand conformation polymorphism technique (PCR-SSCP). We first determined exon/intron boundaries and flanking intronic sequences, and found that the KVLQT1 gene consists of 17 coding exons. Subsequently, we synthesized oligonucleotide primers to cover the coding region and the flanking intronic sequences, and searched for mutations in 31 Japanese LQTS families. When genomic DNA from each proband was examined by PCR-SSCP followed by direct DNA sequencing, mutations were detected in five families; two independent families carried the same mutation and three of the four were novel. Each mutation was present in affected relatives of the respective proband. This work will enable us to search more thoroughly for LQTS mutations associated with KVLQT1, and eventually will help us in finding genotype/phenotype relationships.

DNA Mutational Analysis↗
PubMed1996

Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.

Mitochondrial trifunctional protein (MTP) is a recently identified enzyme involved in mitochondrial beta-oxidation, harboring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain 3-ketothiolase activity. A deficiency of this protein is associated with impaired oxidation of long-chain fatty acids which can lead to sudden infant death. Furthermore, it is clear that this inborn error of fatty acid oxidation is very frequent, second to medium chain acyl-CoA dehydrogenase deficiency. In most patients only the LCHAD activity of MTP is deficient with near normal activity of the two other enzyme activities of the complex. We recently described the occurrence of a frequent G1528C mutation in the cDNA coding for the a subunit of MTP. Using S. cerevisiae for expression of wild type and mutant protein we show that the G1528C mutation is directly responsible for the loss of LCHAD activity. Furthermore, we describe a newly developed method allowing identification of the G1528C mutation in genomic DNA. The finding of an 87% allele frequency of the G1528C mutation in 34 LCHAD deficient patients makes this a valuable test for prenatal diagnosis. Finally, we show that the gene encoding the alpha subunit of MTP is located on chromosome 2p24.1-23.3.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1996

Comparison of spontaneous hprt mutation spectra at the nucleotide sequence level in the endogenous hprt gene and five other genomic positions.

Mutation spectra at the nucleotide sequence level of five hprt cDNA genes integrated in different genomic positions of a HPRT(-) derivative of the human lymphoblastoid TK6 cell line were compared with each other and with the spectrum of mutations confined to the 657 bp coding region of the endogenous hprt gene in the parental TK6 cells. The mutation rates in these genomic positions vary significantly and also the mutation spectra are different. In each genomic position the majority of mutations are basepair substitutions and deletions. the ratios of which vary among the genomic positions. Although it is likely that the different rates of deletion are to a large extent the net result of different rates of misalignment and repair of these errors in the various genomic positions, for the basepair substitutions it is not possible to deduce which mechanisms have caused these mutations and what causes the differences among the genomic positions. Taken together, the differences in mutation rates and spectra cannot be explained by a single mutagenic process.

Cell Line↗
PubMed1999

Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II.

X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-storage disease. XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver. Both types of XLG are caused by mutations in the same gene, PHKA2, that encodes the regulatory alpha subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic structure. The gene consists of 33 exons, spanning >/=65 kb. By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG II, bringing the total to 19 XLG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncation or disruption of the PHKA2 protein. In contrast, all XLG II mutations are missense mutations or small in-frame deletions and insertions. These results suggest that the biochemical differences between XLG I and XLG II might be due to the different nature of the disease-causing mutations in PHKA2. XLG I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas XLG II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.

Base Sequence↗