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PubMed2000

Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts.

DNA mismatch repair (MMR) deficiency leads to an increased mutation frequency and a predisposition to neoplasia. 'Knockout' mice deficient in the MMR proteins Msh2 and Pms2 crossed with mutation detection reporter (supF, lacI and cII) transgenic mice have been used to facilitate a comparison of the changes in mutation frequency and spectra. We find that the mutation frequency was consistently higher in Msh2-deficient mice than Pms2-deficient mice. The lacI target gene, which is highly sensitive to point mutations, demonstrated that both Msh2- and Pms2-deficient mice accumulate transition mutations as the predominant mutation. However, when compared with Msh2(-/-) mice, lacI and cII mutants from Pms2-deficient mice revealed an increased proportion of +/-1 bp frameshift mutations and a corresponding decrease in transversion mutations. The supF target gene, which is sensitive to frameshift mutations, and the cII target gene revealed a strong tendency for -1 bp deletions over +1 bp insertions in Msh2(-/-) compared with Pms2(-/-) mice. These data indicate that Msh2 and Pms2 deficiency have subtle but differing effects on mutation avoidance which may contribute to the differences in tumor spectra observed in the two 'knockout' mouse models. These variances in mutation accumulation may also play a role, in part, in the differences seen in prevalence of MSH2 and PMS2 germline mutations in hereditary non-polyposis colorectal cancer patients.

Adenosine Triphosphatases↗
PubMed1995

TP53 gene mutations and protein accumulation in primary vaginal carcinomas.

Primary carcinomas from 46 patients were screened for TP53 alterations. Immunohistochemistry demonstrated nuclear TP53 protein accumulation in 22 (48%) cases using the polyclonal CM1 antiserum, whereas 15 (33%) cases showed positive nuclear staining with the mononuclear antibody PAb 1801. Constant denaturant gel electrophoresis (CDGE) was used to screen 27 of the vaginal carcinomas for mutations in the conserved regions of the TP53 gene (exons 5-8). Six of these tumours (22%) contained mutations: four were found in exon 5 and two in exon 8. A total of 50% of the primary vaginal carcinomas carried a TP53 alteration. These results indicate that TP53 abnormalities may be involved in the development of these tumours. However, there was no significant association between TP53 abnormalities and survival.

Adult↗
PubMed2005

Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.

Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

Aging↗
PubMed2002

Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism?

In man, cells accumulate somatic mutations of mitochondrial DNA (mtDNA) as part of normal ageing. Although the overall concentration of mutant mtDNA is low in tissue as a whole, very high numbers of various mtDNA mutations develop in individual cells within the same person, which causes age-associated mitochondrial dysfunction. Some tumours contain high numbers of mtDNA mutations that are not present in healthy tissues from the same individual. The proportion of mutant mtDNA also rises in patients with progressive neurological disease due to inherited mtDNA mutations. This increase parallels the relentless clinical progression seen in these disorders. Mathematical models suggest that the same basic cellular mechanisms are responsible for the amplification of mutant mtDNA in ageing, in tumours, and in mtDNA disease. The accumulation of cells that contain high levels of mutant mtDNA may be an inevitable result of the normal mechanisms that maintain cellular concentrations of mtDNA.

Aging↗
PubMed1994

Nuclear accumulation of p53 protein correlates with mutations in the p53 gene on archival paraffin-embedded tissues of human breast cancer.

Fifty invasive ductal carcinomas of the breast were analyzed by immunohistochemistry, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing after microdissection of conventional formalin-fixed, paraffin-embedded tissues. A highly significant association between the presence of p53 gene mutation and nuclear accumulation of p53 protein was found (P < 0.0001). Of 13 tumors that demonstrated p53 gene mutations, 11 (84.6%) showed nuclear accumulation of p53 protein. However, of 37 tumors in which gene mutations were not detected, only 5 (13.5%) showed nuclear accumulation of p53 protein. There was a statistically significant association between the nuclear accumulation of p53 protein and a higher histological grade (P < 0.001) or mitotic index (P < 0.01). In addition, gene mutations had a statistically significant association with a higher histological grade (P < 0.05) or mitotic index (P < 0.0001). Therefore, p53 abnormalities might be associated with an aggressive phenotype in breast cancer. We conclude that the immunohistochemical detection of nuclear p53 protein accumulation is highly associated with p53 gene mutations in archival paraffin-embedded tissues, and that this method is useful for rapid screening of p53 abnormalities.

Base Sequence↗
PubMed1998

[Detection of the p53 protein accumulation and p53 gene mutation in squamous cell carcinoma of the lung].

OBJECTIVE: To investigate the effects of p53 protein accumulation and p53 gene mutation in the pathogenesis of squamous cell carcinoma of lung. METHODS: Immunohistochemistry and PCR-SSCP techniques were used to detect p53 protein accumulation and p53 gene mutation. RESULTS: p53 protein accumulations was found in 52.5% (63/120) of the samples. p53 gene mutation was detected in 56.7% (68/120) of the same specimens by PCR-SSCP. In 24 cases (35.3%, 24/68), the mutations was locating on exon 5, 11 cases (16.2%, 11/68) on exon 6, 18 cases (26.5%, 18/68) on exon 7 and 15 cases (22.1%, 15/68) on exon 8 respectively. The rate of p53 gene mutation/overexpression was 60%. p53 gene mutation/overexpression rate of moderately (63.6%, 28/44) or poorly (63.5%, 40/63) differentiated pulmonary squamous cell carcinoma was significantly higher than that of the well differentiated carcinoma (30.8%, 4/13). In comparing with non-lymph node metastasis group (43.1%, 28/65), p53 gene mutation/overexpression rate in metastasis group (80%, 44/55) was significantly higher. p53 gene mutation/overexpression rate of pulmonary squamous cell carcinoma in advanced stage (76.3%, 45/59) was significantly higher than that in the early stage (44.3%, 27/61). p53 gene mutation/overexpression rate in heavy smoking group (72.4%, 55/76) was significantly higher than that in non-smoking group (38.6%, 17/44). No statistically significant correlation was found between p53 gene mutation/overexpression and sex, age, tumor location or invasion of the surrounding tissue. CONCLUSIONS: p53 gene mutation/overexpression may play an important role in the pathogenesis of squamous cell carcinoma of lung and can be considered as a predicting marker of prognosis.

Adult↗
PubMed2005

Effect of the opaque and floury mutations on the accumulation of dry matter and protein fractions in maize endosperm.

Grains of nine opaque (o) and floury (fl) mutants of maize (Oh43o1, Oh43o2, B79o5, B37o7, W22o10, W22o11, W22o13, Oh43fl1 and Oh43fl2) were examined for the weight proportions of their component tissues and the content of eight nitrogen fractions in their endosperms. A linear regression was found connecting the amounts (mg per endosperm) of zeins and true proteins (crude proteins minus non-protein nitrogen) for the non-opaque2 mutants. The data points connecting zeins to true proteins present in the mature endosperms of six wild-type (+) inbred lines and their o2 versions were located outside (+) or within (o2) the 95% confidence range of the regression line. The data obtained from the developing and mature endosperms of the W22o7 inbred line (Di Fonzo et al., Plant Sci. Lett., 1979, 77) and the floury portion of mature endosperms of three other wild-type inbred lines fell practically on the regression line. The effects of genotype and environmental factors upon the relative accumulation rate of zeins were assessed from the present results and the data taken from the literature concerning the quantitative interdependence between zeins and true proteins in immature and mature endosperms.

Gene Expression Regulation, Plant↗
PubMedDate not supplied

[Evolution of the DNA structure: direction, mechanism, rate].

On the basis of the analysis of frequencies of occurence of pyrimidines of different length, the degree of clustering of DNA of a hundred species belonging to different taxons has been determined. A tendency towards increase in the index of DNA clustering was revealed in the sequence: bacteria, invertebrates, fishes, amphibians, reptiles, birds, mammals. A mechanism is postulated, according to which an increase in the degree of clustering of DNA in the process of progressive evolution of species may be due to accumulation of mutations, Pyr in equilibrium Pur transversions, resulting in an increase in the degree of asymmetry of the complementary chains of DNA. That this mechanism does exist is proved by a positive correlation between the degree of clustering of DNA and the degree of asymmetry of natural DNA chains. The mean frequency of mutation of vertebrates is about 4,6-10(-8) substitutions per nucleotide per year. Evolution of different groups of organisms may be accompanied with an increase in the rate of evolution of DNA structure. With the help of a special computer program, proceeding from the amino acid sequence of cytochromes c in 40 species belonging to different taxons, the degree of clustering of pyrimidines and the degree of asymmetry of complementary chains of DNA cistrons coding for cytochrome c was determined. A general tendency towards an increase in the mean values of the corresponding parametres of structure was found in the following: bacteria, invertebrates, fishes, amphibians, reptiles, birds and mammals. Thus, it was established that "neutral" amino acid substitutions in cytochromes are based on the selection of mutations leading to accumulation of pyrimidines in sense H-chain of DNA, and purines--in the corresponding mRNA. The frequency of mutation in cytochrome c of chordates is about 5,2-10(-8) of amino acid residues per year. It is assumed that the evolution modification of DNA structure may be due to increase in the disturbance stability of translation.

Amino Acids↗
PubMed1992

Small subgroup of aggressive, highly proliferative prostatic carcinomas defined by p53 accumulation.

BACKGROUND: Mutations in the p53 gene resulting in the accumulation of altered p53 proteins with prolonged half-life have been found in a large variety of human malignancies. PURPOSE: We studied the significance of p53 protein accumulation in prostatic carcinoma. METHODS: The material consisted of 137 paraffin-embedded, primary prostatic carcinomas. Accumulation of p53 protein was studied by immunohistochemical staining using a polyclonal p53-specific CM-1 antibody. Proliferation activity was determined by DNA flow cytometry and by immunohistochemical detection of proliferative cell nuclear antigen (PCNA) using a monoclonal PC10 antibody. RESULTS: Eight (6%) of the tumors showed intense p53 staining in more than 20% of the tumor cells, 15 (11%) had only lower level immunoreactivity, and 114 (83%) showed no staining. High-level p53 accumulation was associated with high histologic grade (P less than .001), DNA aneuploidy (P less than .05), and high cell proliferation rate as defined by flow cytometric S-phase analysis (P less than .01) or PCNA expression (P less than .01). High-level p53 accumulation predicted short, progression-free interval (P less than .01) and poor survival (P less than .001), with about a 12-fold relative risk of death as compared with p53-negative cases. Low-level p53 accumulation had no prognostic significance. CONCLUSIONS: Accumulation of p53 confers proliferative advantage for prostatic carcinoma cells and defines a small subgroup of highly malignant carcinomas.

Aged↗
PubMed1996

Frequent TP53 gene alterations (mutation, allelic loss, nuclear accumulation) in primary non-small cell lung cancer.

Mutations of the TP53 tumour suppressor gene have been reported for many human cancers. A variety of TP53 mutations have also been reported for both primary non-small cell lung cancer (NSCLC) and associated metastases. To assess the pathogenetic significance of TP53 gene alterations in NSCLC, 24 paired samples of primary NSCLC and the corresponding normal lung tissue were analysed for mutations of the TP53 gene (exons 5-8) using exon-specific PCR, single-strand conformation polymorphism PCR (SSCP-PCR) and direct DNA sequencing; for p53 protein accumulation by immunohistochemistry and for 17p allelic loss using restriction fragment length polymorphism (RFLP) probes on Southern blots and amplified fragment length polymorphism-PCR. TP53 point mutations were observed in 9/24 (38%) tumours encompassing a total of 14 mutations. Two tumours displayed the same double mutation while a third harboured four different mutations. Seventeen of 24 NSCLCs (71%) overexpressed p53 protein and all 17 immunopositive tumours (100%) showed a mutation and/or allelic loss at the D17S30 locus. Of the 17 NSCLCs informative at the DS17S30 locus, 10 (59%) showed allelic loss, of which five (50%) were also mutated on the remaining TP53 allele. These results suggest that TP53 gene alterations are involved in the pathogenesis of primary NSCLC and that such alterations may serve a selective role in the development of NSCLC by diminishing the apoptotic potential of bronchial epithelial cells heterozygous for a TP53 point mutation. This may also explain the accumulation of multiple TP53 point mutations in 3/24 of our NSCLC samples.

Alleles↗
PubMed1985

Plasmid-borne Tn5 insertion mutation resulting in accumulation of gentisate from salicylate.

Plasmid-borne Tn5 insertion mutants of a Pseudomonas species which accumulated 2,5-dihydroxybenzoate (gentisate) following growth on 2-hydroxybenzoate (salicylate) were obtained from a pool of mutants that were unable to grow on naphthalene. One such mutant was characterized further. The ability of this mutant to oxidize gentisate was 100-fold less than the ability of a Nah+ Sal+ strain harboring the unmutagenized plasmid, although both strains oxidized and grew on salicylate. These bacteria were presumably able to metabolize salicylate via catechol, since they possessed an inducible, plasmid-encoded catechol 2,3-dioxygenase. Our results suggest that there is an alternate, plasmid-encoded route of salicylate degradation via gentisate and that some plasmid-associated relationship between this pathway and naphthalene oxidation exists.

Catechol 2,3-Dioxygenase↗
PubMed1997

TP53 protein accumulation and gene mutation in relation to overexpression of MDM2 protein in ovarian borderline tumours and stage I carcinomas.

Three hundred and seventy-four early-stage ovarian tumours, including 27 borderline tumours and 347 stage I carcinomas, were investigated immunohistochemically for overexpression of the TP53 and MDM2 proteins. TP53 (p53) and MDM2 alterations were detected in 15 and 4 per cent of borderline tumours, and in 50 and 13 per cent of stage I carcinomas, respectively. Mutations in the TP53 gene (exons 5-8) were demonstrated in 29 of the 50 stage I carcinomas studied, using denaturing gel electrophoresis followed by direct sequencing. TP53 overexpression was seen less often in tumours of mucinous and endometrioid type than in tumours of other histological types and more often in moderately and poorly differentiated than in well differentiated tumours. MDM2 protein overexpression was seen more often in clear cell carcinoma than in tumours of other histological types. These results indicate that TP53 abnormalities play a crucial role, and MDM2 abnormalities a minor role, in the development of early-stage ovarian carcinoma. There was no significant association between TP53 or MDM2 alterations and survival in multivariate analysis.

Adolescent↗
PubMed2000

Theory of evolutionary molecular engineering through simultaneous accumulation of advantageous mutations.

We examined the effectiveness of an "adaptive leap" strategy using the "mutation scrambling" method as an efficient optimization technique (Uchiyama, 2000;J. Biochem.128, 441-447) for cases where mutational (rough) additivity holds in fitness. The mutation scrambling method is composed of the following three processes: (1) preliminary selection of several advantageous single-point mutations introduced in a wild-type sequence; (2) preparation of various multiple-point mutants incorporating the advantageous mutant residue or wild-type residue at each of the selected sites, by scrambling the mutant residues and wild-type residues (this process is called mutation scrambling); and (3) selection of the fittest through screening of the mutant pool. The fitness distribution in the mutant pool is controlled by the mixing ratio of the mutant residues to the wild-type residues. We focused on the mutant fitness distribution and obtained the optimal mixing ratio which efficiently generates superior multiple-point mutants with high fitnesses. As a result, we found that the optimal ratio lies between 7/3 and 9/1 in realistic cases. Particularly, this strategy works well in cases where the number of component mutations is large and the size of the population to be screened is small. Analysis of the mutant fitness distributions with various mixing ratios is also useful to explore local fitness landscapes.

Animals↗
PubMed1986

Accumulated measles virus mutations in a case of subacute sclerosing panencephalitis: interrupted matrix protein reading frame and transcription alteration.

Subacute sclerosing panencephalitis (SSPE) is a fatal disease affecting the human central nervous system several years after acute measles infection. Measles virus (MV) genomes replicating in SSPE brains do not give rise to budding particles and present various defects in gene expression, mostly concerning the matrix (M) protein. For one SSPE case (K), shown previously to be devoid of M protein expression, we examined here in detail the features involved in this defect. In the brain of patient K the normal, monocistronic MV M mRNA was completely substituted by a bicistronic RNA containing the coding sequence of the preceding phosphoprotein (P) gene in addition to the M coding sequence. Analysis of the P-M intercistronic region by direct cDNA sequencing showed that the consensus sequence at this RNA processing site was unaltered but revealed several distant point mutations. cDNA cloning and sequencing of the entire M coding region established that one of the point mutations leads to a stop codon at triplet 12 of the M reading frame. It is unknown whether this defect, explaining by itself the lack of M protein, is related also to the block of M mRNA formation. In addition we note that as much as 1% of the nucleotides differed between two overlapping clones from the same brain. This high sequence variability could possibly account for the diversity of defects observed in MV gene expression in SSPE brains and may be a general phenomenon associated with RNA virus persistence.

Amino Acid Sequence↗
PubMed2006

The accumulation of deleterious mutations in rice genomes: a hypothesis on the cost of domestication.

The extent of molecular differentiation between domesticated animals or plants and their wild relatives is postulated to be small. The availability of the complete genome sequences of two subspecies of the Asian rice, Oryza sativa (indica and japonica) and their wild relatives have provided an unprecedented opportunity to study divergence following domestication. We observed significantly more amino acid substitutions during rice domestication than can be expected from a comparison among wild species. This excess is disproportionately larger for the more radical kinds of amino acid changes (e.g. Cys<-->Tyr). We estimate that approximately a quarter of the amino acid differences between rice cultivars are deleterious, not accountable by the relaxation of selective constraints. This excess is negatively correlated with the rate of recombination, suggesting that 'hitchhiking' has occurred. We hypothesize that during domestication artificial selection increased the frequency of many deleterious mutations.

Crops, Agricultural↗
PubMed1998

A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA(Trp) gene.

We detected a novel pathogenic mutation, a G-->A transition at position 5521 of mitochondrial tRNA(Trp) gene, in association with familial late-onset mitochondrial myopathy. The mutation was detected in muscle but not in leukocytes from the family's proband. Morphological and biochemical studies documented a severe defect of muscle cytochrome c oxidase (COX) activity. RFLP analysis of single muscle fibers demonstrated segregation of higher percentages of mutated genomes in COX-negative ragged red fibres compared with normal fibers. A predominant impairment in synthesis of subunits I and III of complex IV due to their highest relative content of tryptophane might explain the greater susceptibility of complex IV to the pathogenic effect of this mutation. A progressive accumulation of mutated genomes in muscle can account for the late onset of symptoms observed in affected members.

Aged↗