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PubMed1977

Accumulation of deleterious genes in a cage population of Drosophila melanogaster.

Lethal and sterility mutations were accumulated in a cage population which was initiated with lethal- and sterility-free second chromosomes of D. melanogaster. It took about 2,000 days for the frequencies of these genes to reach equilibrium levels, i.e., 18% lethal and 9% male-sterile chromosomes. Two other cage populations which were initiated with random chromosomes sampled from natural populations and kept for more than eleven years in the laboratory showed 19-20% lethal content. The elimination rates of lethals by homozygosis in these populations were smaller than the mutation rate. By using NEI's formulae, the deleterious effect of a lethal gene in heterozygous condition (h) was estimated to be 0.035. The effective population number in the cage populations was estimated to be 1,000-2,900, while the actual population number was 3,500-7,800.

Alleles↗
PubMed2005

Genetic variation and dynamics of hepatitis C virus replicons in long-term cell culture.

Hepatitis C virus (HCV) genomic sequences are known to vary widely among HCV strains, but to date there have been few reports on the genetic variations and dynamics of HCV in an experimental system of HCV replication. In this study, a genetic analysis of HCV replicons obtained in long-term culture of two HCV replicon cells (50-1 and 1B-2R1), which were established from two HCV strains, 1B-1 and 1B-2, respectively, was performed. One person cultured 50-1 cells for 18 months, and two people independently cultured 50-1 cells for 12 months. 1B-2R1 cells were also cultured for 12 months. The whole nucleotide sequences of the three independent replicon RNA clones obtained at several time points were determined. It was observed that genetic mutations in both replicons accumulated in a time-dependent manner, and that the mutation rates of both replicons were approximately 3.0 x 10(-3) base substitutions/site/year. The genetic diversity of both replicons was also enlarged in a time-dependent manner. The colony formation assay by transfection of total RNAs isolated from both replicon cells at different time points into naive HuH-7 cells revealed that the genetic mutations accumulating with time in both replicons apparently improved colony formation efficiency. Taken together, these results suggest that the HCV replicon system is useful for the analysis of evolutionary dynamics and variations of HCV. Using this replicon cell culture system, it was demonstrated further that neither ribavirin nor its derivative mizoribine accelerated the mutation rate or the increase in the genetic diversity of HCV replicon.

Cell Culture Techniques↗
PubMed2005

Expression of metallothoinein isoform 3 is restricted at the post-transcriptional level in human bladder epithelial cells.

This study was designed to define the effect that overexpression of MT-3 would have on a cell culture model of bladder urothelium. Stable and inducible transfection was used to achieve overexpression of the MT-3 gene in the UROtsa cell line. When the UROtsa cells were stably transfected with the MT-3 coding sequence, there was highly elevated expression of MT-3 mRNA, but no MT-3 protein. An inducible vector showed that low basal levels of MT-3 mRNA and protein could be produced, but that induction only increased MT-3 mRNA and not protein. The clones expressing low basal levels of MT-3 protein also had reduced growth rates compared to control cells. Site directed mutagenesis was used to produce an MT-3 coding sequence where the prolines in positions 7 and 9 were converted to threonines. When this altered MT-3 was stably transfected into the UROtsa cells, the cells were able to accumulate the mutated form of the MT-3 protein. These studies show that MT-3 protein expression is inhibited by post-transcriptional control in the urothelial cell. Modifying the MT-3 protein to resemble the MT-1 isoform removes this component of post-transcriptional control and allows accumulation of the mutated MT-3 protein. The altered sequence involved in post-transcriptional control of MT-3 protein expression is the same sequence implicated in the neuronal growth inhibitory activity associated specifically with the MT-3 isoform of the MT gene family.

Cadmium↗
PubMed1991

The Staphylococcus aureus mutation pcrA3 leads to the accumulation of pT181 replication initiation complexes.

In Staphylococcus aureus cells carrying the pcrA3 chromosomal mutation, plasmid pT181 and its derivatives were maintained at a reduced copy number. A significant proportion of their DNA migrated during agarose gel electrophoresis as nicked DNA. The results obtained in the characterization of this plasmid DNA species show that it represents replication initiation complexes. Such complexes could not be detected in a wild-type host. The replication initiation complexes present in pcrA3 cells could resume replication after a lag. It was concluded from these results that the pcrA3 host mutation affected a step in plasmid pT181 replication immediately following the formation of the replication initiation complex, and that in pcrA3 this step became rate-limiting for plasmid pT181 replication.

Bacterial Proteins↗
PubMed2000

p53 Antibodies in the sera of patients with various types of cancer: a review.

p53 antibodies (p53-Abs) were discovered 20 years ago during the course of tumor-associated antigens screening. The discovery of p53 mutation and accumulation of p53 in human tumors shed new light on the p53 humoral response. In the present review, we have compiled more than 130 papers published in this specific field since 1992. We demonstrate that p53-Abs are found predominantly in human cancer patients with a specificity of 96%. Such antibodies are predominantly associated with p53 gene missense mutations and p53 accumulation in the tumor, but the sensitivity of such detection is only 30%. It has been demonstrated that this immune response is due to a self-immunization process linked to the strong immunogenicity of the p53 protein. The clinical value of these antibodies remains subject to debate, but consistent results have been observed in breast, colon, oral, and gastric cancers, in which they have been associated with high-grade tumors and poor survival. The finding of p53-Abs in the sera of individuals who are at high risk of cancer, such as exposed workers or heavy smokers, indicates that they have promising potential in the early detection of cancer.

Autoantibodies↗
PubMed1997

Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human colorectal and gastric carcinomas.

Mutations within microsatellite sequences, consisting of additions or deletions of repeat units, are known as the replication/repair error positive (RER+) phenotype or micorsatellite instability (MI). Microsatellite instability has been demonstrated in hereditary and sporadic colorectal carcinomas and is usually observed in noncoding regions of genomic DNA. However, relatively few coding region targets of MI have been identified thus far. Using PCR, we amplified regions encompassing (A)8 and (C)8 microsatellite tracts within hMSH3 and hMSH6 from 31 RER+ sporadic colorectal tumors, 8 hereditary colon cancers, 23 RER+ gastric carcinomas, and 32 RER- gastric tumors. Mutations were found in 11 (36%) of 31 sporadic colon carcinomas, 4 (50%) of 8 hereditary colorectal cancers, and 5 (22%) of 23 RER+ gastric carcinomas, but in only 2 (6%) of 32 RER- gastric carcinomas. These frameshift mutations cause premature stop codons downstream that are predicted to abolish normal protein function. Our results and those of others suggest that DNA mismatch repair genes, such as hMSH3 and hMSH6, are targets for the mutagenic activity of upstream mismatch repair gene mutations and that this enhanced genomic instability may accelerate the accumulation of mutations in RER+ tumors.

Adenocarcinoma↗
PubMed2003

Increased frequency of gastrin-releasing peptide receptor gene mutations during colon-adenocarcinoma progression.

Epithelial cells lining the mature human colon do not normally express receptors for gastrin-releasing peptide (GRPR). In contrast, we have shown that when aberrantly expressed in functional form in colon cancer, this protein acted as a morphogen where it caused tumor cells to adopt a better-differentiated phenotype. Importantly, GRPR mRNA is ubiquitously mutated in human colon cancer cell lines, with inactivating mutations detected in all cell lines not expressing functional receptor. Since colon cancers are heterogeneously differentiated, we set out to determine if the GRPR gene was mutated as a function of tumor cell differentiation in archived human colon cancers. We used laser capture microscopy to dissect out 67 regions of defined differentiation from 20 human colon cancers randomly selected from the UIC GI Tumor Bank. Except for two polymorphisms, the GRPR gene was not mutated in nonmalignant epithelial cells. In contrast, 42 distinct mutations were identified in malignant cells. Overall mutation number inversely correlated with the degree of tumor cell differentiation. Within any cancer, all GRPR mutations found within better-differentiated cells were conserved in more poorly-differentiated cells; while all poorly-differentiated cells contained mutations resulting in GRPR pharmacological inactivation. These data suggest that accumulation of mutations within the GRPR gene ultimately resulting in the production of nonfunctional receptors may represent a previously unappreciated mechanism allowing for the dedifferentiation of tumor cells within any particular colon cancer; and that poorly-differentiated tumor cells within any individual cancer may arise clonally from their better-differentiated precursors.

Adenocarcinoma↗
PubMed1972

Selection in finite populations with multiple alleles. 3. Genetic divergence with centripetal selection and mutation.

Natural selection for an intermediate level of gene or enzyme activity has been shown to lead to a high frequency of heterotic polymorphisms in populations subject to mutation and random genetic drift. The model assumes a symmetrical spectrum of mutational variation, with the majority of variants having only minor effects on the probability of survival. Each mutational event produces a variant which is novel to the population. Allelic effects are assumed to be additive on the scale of enzyme activity, heterosis arising whenever a heterozygote has a mean level of activity closer to optimal than that of other genotypes in the population.-A new measure of genetic divergence between populations is proposed, which is readily interpreted genetically, and increases approximately linearly with time under centripetal selection, drift and mutation. The parameter is closely related to the rate of accumulation of mutational changes in a cistron over an evolutionary time span.-A survey of published data concerning polymorphic loci in man and Drosophila suggests than an alternative model, based on the superiority of hybrid molecules, is not of general importance. Thirteen loci giving rise to hybrid zones on electrophoresis have a mean heterozygote frequency of 0.22 +/-.06, compared with a value of 0.23 +/-.04 for 16 loci classified as producing no hybrid enzyme.

Alleles↗
PubMed2003

Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes.

Point mutation rates in exons (synonymous sites) and noncoding (introns and intergenic) regions are generally assumed to be the same. However, comparative sequence analyses of synonymous substitutions in exons (81 genes) and that of long intergenic fragments (141.3 kbp) of human and chimpanzee genomes reveal a 30%-60% higher mutation rate in exons than in noncoding DNA. We propose a differential CpG content hypothesis to explain this fundamental, and seemingly unintuitive, pattern. We find that the increased exonic rate is the result of the relative overabundance of synonymous sites involved in CpG dinucleotides, as the evolutionary divergence in non-CpG sites is similar in noncoding DNA and synonymous sites of exons. Expectations and predictions of our hypothesis are confirmed in comparisons involving more distantly related species, including human-orangutan, human-baboon, and human-macaque. Our results suggest an underlying mechanism for higher mutation rate in GC-rich genomic regions, predict nonlinear accumulation of mutations in pseudogenes over time, and provide a possible explanation for the observed higher diversity of single nucleotide polymorphisms (SNPs) in the synonymous sites of exons compared to the noncoding regions.

Animals↗
PubMed1993

In vivo mutations in human blood cells: biomarkers for molecular epidemiology.

Mutations arising in vivo in recorder genes of human blood cells provide biomarkers for molecular epidemiology by serving as surrogates for cancer-causing genetic changes. Current markers include mutations of the glycophorin-A (GPA) or hemoglobin (Hb) genes, measured in red blood cells, or mutations of the hypoxanthine-guanine phosphoribosyltransferase (hprt) or HLA genes, measured in T-lymphocytes. Mean mutant frequencies (variant frequencies) for normal young adults are approximately: Hb (4 x 10(-8)) < hprt (5 x 10(-6)) = GPA (10 x 10(-6)) < HLA (30 x 10(-6)). Mutagen-exposed individuals show decided elevations. Molecular mutational spectra are also being defined. For the hprt marker system, about 15% of background mutations are gross structural alterations of the hprt gene (e.g., deletions); the remainder are point mutations (e.g., base substitutions or frameshifts). Ionizing radiations result in dose-related increases in total gene deletions. Large deletions may encompass several megabases as shown by co-deletions of linked markers. Possible hprt spectra for defining radiation and chemical exposures are being sought. In addition to their responsiveness to environmental mutagens/carcinogens, three additional findings suggest that the in vivo recorder mutations are relevant in vivo surrogates for cancer mutations. First, a large fraction of GPA and HLA mutations show exchanges due to homologous recombination, an important mutational event in cancer. Second, hprt mutations arise preferentially in dividing T-cells, which can accumulate additional mutations in the same clone, reminiscent of the multiple hits required in the evolution of malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1997

Mechanisms underlying mismatch repair deficiencies in normal cells.

Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition which is linked to heterozygous mutations in mismatch repair genes. HNPCC tumour cells, in which the remaining wild-type copy of the mismatch repair gene is inactivated, display instability of microsatellite markers reflecting a defect in mismatch repair. Recently, patients carrying either one of two distinct germline mutations in the MLH1 and PMS2 genes were reported to accumulate somatic mutations of microsatellites in untransformed cells. One of the mechanisms that might account for this phenomenon was a dominant negative effect of the mutant allele. To evaluate this possibility, we examined a different family carrying one of the mutations (deletion of codon 618K in the MLH1 gene) which has been suspected to induce genetic instability in untransformed cells. No mutations in dinucleotide repeat markers were observed in a large number of lymphoblast clones derived from a carrier. Evidence for the deletion of the wild-type allele in two different tumours suggested that the inactivation of both gene copies was required for tumour initiation. These results indicate that the MLH1 618K deletion mutation alone does not necessarily cause marked mismatch repair deficiency in the presence of a wild-type allele.

Adaptor Proteins, Signal Transducing↗
PubMed1967

Thiamine-dependent accumulation of tetramethylpyrazine accompanying a mutation in the isoleucine-valine pathway.

A mutant of Corynebacterium glutamicum was found to accumulate high concentrations of a material which crystallized upon cooling of the broth. The compound was identified as tetramethylpyrazine. The mutant was found to require isoleucine, valine, leucine, and pantothenate for growth. All four requirements probably result from the loss of a single enzyme of the isoleucine-valine pathway. Since similar mutants of Neurospora crassa accumulate acetoin, the present mutant probably forms tetramethylpyrazine from acetoin. Accumulation of tetramethylpyrazine was dependent upon addition of thiamine. This observation is consistent with the known activity of diphosphothiamine as a cofactor for the formation of acetolactate (a precursor of acetoin) from pyruvate.

Corynebacterium↗
PubMed2004

Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A.

Mice expressing an error-prone mitochondrial DNA polymerase rapidly accumulate random mutations in mitochondrial DNA. Expression of the transgene in the heart leads to dilated cardiomyopathy accompanied by a wave of apoptosis in cardiomyocytes, and a vigorous and persistent protective response, including upregulation of the anti-apoptotic protein, Bcl-2. To investigate the role of the mitochondrial permeability transition pore in the development of disease, we treated mice with cyclosporin A (CsA), an inhibitor of pore opening. Drug treatment prevented cardiac dilatation, transgene-specific apoptosis, and upregulation of Bcl-2. It also rescued hearts from the profound decrease in connexin 43, which characterizes the dilatated heart. Treatment with FK506, which like CsA inhibits cytoplasmic calcineurin but not the mitochondrial pore, did not affect disease development, suggesting that the relevant target of CsA was the mitochondrial pore. These data implicate breakdowns in the mitochondrial permeability barrier in pathogenesis of elevated frequencies of mtDNA mutations.

Animals↗
PubMed1994

The capacity for growth stimulation by TGF beta 1 seen only in advanced colon cancers cannot be ascribed to mutations in APC, DCC, p53 or ras.

Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and mutations in the dominant oncogene K-ras, with loss of wild type alleles. In earlier studies we had observed that about half of the resected human colon cancers placed into primary culture were growth stimulated by TGF beta 1. This group included the more advanced cancers which were either poorly differentiated primary-site cancers or metastases. In contract, the more differentiated colon cancers were inhibited or unaffected by TGF beta 1, indicating that a switch in response to TGF beta 1 occurs during colon cancer progression. Different sublines of the HT29 colon carcinoma cell line model the resected cancers, responding to TGF beta 1 by proliferation, inhibition or no growth modulation. The current study shows that while the poorly differentiated, TGF beta 1-stimulated sublines are most tumorigenic, all the sublines have the same spectrum of mutations: truncating mutations in both APC (adenomatous polyposis coli) alleles, no activated ras genes, mutated and thus overexpressed p53, and very low expression of DCC compared to normal colon cells. Genes other than the four already implicated in colon carcinoma evolution are responsible for the mitogenic response to TGF beta 1 found in the more advanced cancers.

Base Sequence↗
PubMed1992

[Aberrations of the p53 antioncogene in malignant tumors].

The results of the present study of the p53 antioncogene in a broad panel of human cell lines (n = 32) and biopsy specimens (n = 435) from both normal and tumour tissues can be summarized as follows: 1. Cells in primary cultures from normal tissues express very low levels of the p53 protein while strong nuclear accumulation of p53 can be seen in all SV 40 transformed human cell lines and the vast majority of tumour--derived cell lines studied. 2. Similarly, in human tissues strong nuclear p53 expression is found in high proportion of malignancies of various histogenesis, in contrast to benign lesions, nonmalignant tissues surrounding malignant tumours and normal tissues in which the p53 protein levels remain below the limits detectable by common immunohistochemical methods. 3. Sequence analysis of p53 mRNA amplified by polymerase chain reaction (PCR) revealed point mutations in the central region of the p53 gene in several cancer cell lines. Furthermore, very good correlation was found between the presence of such mutations and accumulation of the mutated p53 protein. This study confirms and extends our current view of p53 as the gene most frequently altered in human cancer and suggests that simple immunohistochemical methods can be used to screen for aberrations of this antioncogene.

Genes, p53↗
PubMed2002

How mitochondrial damage affects cell function.

The pathophysiology of mitochondrial DNA (mtDNA) diseases is caused by increased cell death and dysfunction due to the accumulation of mutations to mtDNA. While the disruption of oxidative phosphorylation is central to mtDNA diseases, many other factors, such as Ca(2+) dyshomeostasis, increased oxidative stress and defective turnover of mitochondrial proteins, may also contribute. The relative importance of these processes in causing cell dysfunction and death is uncertain. It is also unclear whether these damaging processes lead to the disease phenotype through affecting cell function, increasing cell death or a combination of both. These uncertainties limit our understanding of mtDNA disease pathophysiology and our ability to develop rational therapies. Here, we outline how the accumulation of mtDNA mutations can lead to cell dysfunction by altering oxidative phosphorylation, Ca(2+) homeostasis, oxidative stress and protein turnover and discuss how these processes affect cell function and susceptibility to cell death. A better understanding of these processes will eventually clarify why particular mtDNA mutations cause defined syndromes in some cases but not in others and why the same mutation can lead to different phenotypes.

Animals↗
PubMed1999

Loss of p53 in F-MuLV induced-erythroleukemias accelerates the acquisition of mutational events that confers immortality and growth factor independence.

Erythroleukemias induced by Friend Murine Leukemia Virus (F-MuLV) involve the insertional activation of the proto-oncogene Fli-1, and the inactivation of the p53 tumor suppressor gene. While the activation of Fli-1 is an early, primary transforming event, p53 mutations are correlated with the immortalization of erythroleukemic cells in culture. In this study we have further analysed the role of p53 loss in F-MuLV induced erythroleukemias by examining the progression of this disease in p53 deficient mice. We found that p53-/- mice succumb to the disease more rapidly than p53+/+ littermates. Additionally, of the 112 tumors generated, 19 gave rise to immortal cell lines, eight of which were derived from p53-/- mice, and ten of which were from p53+/- mice. The ability of these primary tumor cells to grow in culture was associated with the complete loss of wild-type p53 in these cell lines. However, cells from many of the tumors induced in p53-/- hosts did not survive in vitro. These results suggest that the loss of p53 does not directly immortalize tumor cells. Instead, we have evidence to suggest that the loss of p53 promotes the accumulation of mutations that are required for survival in culture and that are capable of accelerating tumor progression in vivo. Indeed, mutations causing expression of the growth factor gene erythropoietin (Epo), were detected in two of seven Epo-independent cell lines from p53 deficient primary erythroleukemias. Moreover, the mechanism of activation of the Epo gene in one of these two Epo-independent cell lines involved genomic rearrangement, that is a hallmark of genetic instability. We propose that, in F-MuLV induced-erythroleukemias, p53 loss may encourage the accumulation of further mutations, subsequently conferring a growth advantage and immortality to the transformed erythroblasts.

Animals↗
PubMed2005

Dynamics of colorectal cancer.

Colorectal cancer results from an accumulation of mutations in tumor suppressor genes and oncogenes. An additional defining characteristic of colorectal cancer is its genetic instability. Two main types of genetic instability have been identified. Microsatellite instability leads to an increased point mutation rate, whereas chromosomal instability refers to an enhanced rate of accumulating gross chromosomal aberrations. All colon cancer cell lines are genetically unstable. An interesting question is whether genetic instability arises early in tumorigenesis. An early emergence of genetic instability could drive most of the somatic evolution of cancer. Here, we review mathematical models of colorectal tumorigenesis and discuss the role of genetic instability.

Colorectal Neoplasms↗