28 results on '"KRONTIRIS, T. G."'
Search Results
2. BCL2 oncogene translocation is mediated by a chi-like consensus.
- Author
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Wyatt, R T, primary, Rudders, R A, additional, Zelenetz, A, additional, Delellis, R A, additional, and Krontiris, T G, additional
- Published
- 1992
- Full Text
- View/download PDF
3. PCR candidate region mismatch scanning: adaptation to quantitative, high-throughput genotyping.
- Author
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Beaulieu, M, Larson, G P, Geller, L, Flanagan, S D, and Krontiris, T G
- Abstract
Linkage and association analyses were performed to identify loci affecting disease susceptibility by scoring previously characterized sequence variations such as microsatellites and single nucleotide polymorphisms. Lack of markers in regions of interest, as well as difficulty in adapting various methods to high-throughput settings, often limits the effectiveness of the analyses. We have adapted the Escherichia coli mismatch detection system, employing the factors MutS, MutL and MutH, for use in PCR-based, automated, high-throughput genotyping and mutation detection of genomic DNA. Optimal sensitivity and signal-to-noise ratios were obtained in a straightforward fashion because the detection reaction proved to be principally dependent upon monovalent cation concentration and MutL concentration. Quantitative relationships of the optimal values of these parameters with length of the DNA test fragment were demonstrated, in support of the translocation model for the mechanism of action of these enzymes, rather than the molecular switch model. Thus, rapid, sequence-independent optimization was possible for each new genomic target region. Other factors potentially limiting the flexibility of mismatch scanning, such as positioning of dam recognition sites within the target fragment, have also been investigated. We developed several strategies, which can be easily adapted to automation, for limiting the analysis to intersample heteroduplexes. Thus, the principal barriers to the use of this methodology, which we have designated PCR candidate region mismatch scanning, in cost-effective, high-throughput settings have been removed.
- Published
- 2001
- Full Text
- View/download PDF
4. The BCL2 major breakpoint region is a sequence- and cell-cycle-specific binding site of the Ku antigen.
- Author
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DiCroce, P A and Krontiris, T G
- Abstract
The majority of translocations involving BCL2 are very narrowly targeted to three breakpoint clusters evenly spaced over a 100-bp region of the gene's terminal exon. We have recently shown that the immediate upstream boundary of this major breakpoint region (mbr) is a specific recognition site for single-strand DNA (ssDNA) binding proteins on the sense and antisense strands. The downstream flank of the mbr is a helicase binding site. In this report we demonstrate that the helicase and ssDNA binding proteins show reciprocal changes in binding activity over the cell cycle. The helicase is maximally active in G1 and early S phases; the ssDNA binding proteins are maximally active in late S and G2/M phases. An inhibitor of helicase binding appears in late S and G2/M. Finally, at least one component of the helicase binding complex is the Ku antigen. Thus, a protein with helicase activity implicated in repair of double-strand breaks, variable (diversity) joining recombination, and, potentially, cell-cycle regulation is targeted to the BCL2 mbr.
- Published
- 1995
- Full Text
- View/download PDF
5. Transforming activity of human tumor DNAs.
- Author
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Krontiris, T G and Cooper, G M
- Abstract
High molecular weight DNAs of 26 human tumors and tumor cell lines were assayed for the presence of transmissible activated transforming genes by transfection of NIH 3T3 mouse cells. DNAs of two bladder carcinoma cell lines induced transformation with high efficiencies (approximately 0.2 transformant per microgram of DNA), whereas DNAs of the other tumors studied lacked detectable transforming activity. These findings suggest that dominant mutations or gene rearrangements can result in the activation of cellular transforming genes in some human tumors.
- Published
- 1981
- Full Text
- View/download PDF
6. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses.
- Author
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Der, C J, Krontiris, T G, and Cooper, G M
- Abstract
Blot hybridization analysis indicated that NIH 3T3 mouse bladder transformed by high molecular weight DNAs of a human bladder and a human lung carcinoma cell line contained new sequences homologous, respectively, to the transforming genes of Harvey (rasH) and Kirsten (rasK) sarcoma viruses. The unique ras sequences were present in multiple independent NIH cell lines transformed in both primary and secondary transfection assays and corresponded to ras sequences normally present in human DNAs. The ras gene product was expressed in NIH cells transformed by bladder carcinoma DNAs and in the human bladder carcinoma cell lines at levels 2- to 4-fold greater than the level observed in nontransformed NIH 3T3 cells. These results indicate that the transforming genes of these human tumor cell lines are the cellular homologs of two retroviral transforming genes.
- Published
- 1982
- Full Text
- View/download PDF
7. A family of short, interspersed repeats is associated with tandemly repetitive DNA in the human genome.
- Author
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Mermer, B, Colb, M, and Krontiris, T G
- Abstract
A family of short, interspersed repeats in the human genome, designated the Mst II family, is described. The canonical structure of the repeat consists of a 220-base-pair (bp) left arm joined to a 160-bp right arm by a 39-bp junction sequence. The right arm is absent in some isolates. Some homology with the "O" and "THE" (transposon-like element) families of repeats was observed, suggesting that the Mst II elements could be a subgroup of a SINE superfamily. The 39-bp junction sequence is tandemly repeated in one of our clones. The association of tandemly repetitive sequences with Mst II elements or the putative superfamily is probably nonrandom; a search of DNA sequence data bases revealed that approximately 80 bp of the Mst II left arm occurs immediately adjacent to the tandem repeat that comprises the human homologue to the BK virus enhancer. The fortuitous occurrence of a gene duplication event involving an Mst II repeat has allowed us to estimate a mutation rate for human DNA.
- Published
- 1987
- Full Text
- View/download PDF
8. LETTERS.
- Author
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SMITH, GREGG, KRONTIRIS, T. G., HARWIN, STEVEN F., BALTIMORE, DAVID, BAZELL, ROBERT, BROCKWAY, NANCY, BRAVO, ELLEN, RENDSBURG, GARY A., DEARINGER, DAVID B., and GREENBERG, ARTHUR
- Published
- 2022
9. Human hypervariable sequences in risk assessment: rare Ha-ras alleles in cancer patients.
- Author
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Krontiris, T G, primary, DiMartino, N A, additional, Mitcheson, H D, additional, Lonergan, J A, additional, Begg, C, additional, and Parkinson, D R, additional
- Published
- 1987
- Full Text
- View/download PDF
10. Human hypervariable sequences in risk assessment: rare Ha-ras alleles in cancer patients
- Author
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Begg, C., DiMartino, N. A., Krontiris, T. G., Lonergan, J. A., Mitcheson, H. D., and Parkinson, D. R.
- Subjects
CANCER ,RISK assessment - Published
- 1987
11. LETTERS.
- Author
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POOR, GEOFFREY S., FENIG, DORIS, CUTHBERTSON, KEN, KRONTIRIS, T. G., BALDWIN, DAVID, BAPNA, MANISH, and VINIK, NINA
- Subjects
- *
POWER (Social sciences) , *PUBLIC officers , *MEMORY , *AMERICANS - Published
- 2024
12. Expression and replication timing patterns of wildtype and translocated BCL2 genes.
- Author
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Sun Y, Wyatt RT, Bigley A, and Krontiris TG
- Subjects
- Alleles, Cell Cycle genetics, Cell Line, DNA Replication, DNA, Neoplasm, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Fluorescence methods, Polymerase Chain Reaction methods, Transcription, Genetic, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Translocation, Genetic
- Abstract
Translocation of the BCL2 gene from chromosome 18 to chromosome 14 results in constitutive expression of the gene. We have recently demonstrated that the major breakpoint region (mbr) of BCL2, which is implicated in 70% of t(14;18) translocations present in human follicular lymphoma, is a matrix attachment region. Since these regions are implicated in control of both transcription and replication, we wished to determine whether BCL2 translocation was also accompanied by changes in replication timing of the translocated allele. Using both fluorescence in situ hybridization and allele-specific PCR, we have demonstrated that the translocated allele replicates at the G1/S boundary, while the wildtype allele continues to replicate as usual in mid-S phase. These differences are accompanied by allele-specific changes in BCL2 expression. Since the net structural effect of t(14;18) translocations within the mbr is to disrupt the BCL2 MAR and replace it with the IGH MARs located just downstream of each breakpoint, we conclude that MAR exchange is a significant, selectable outcome of these translocations. We propose that subsequent changes of replication and transcriptional patterns for the translocated BCL2 allele result from this exchange and represent important early steps in lymphomagenesis., (Copyright 2001 Academic Press.)
- Published
- 2001
- Full Text
- View/download PDF
13. Re: HRAS1 rare minisatellite alleles and breast cancer in Australian women under age forty years.
- Author
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Krontiris TG
- Subjects
- Adult, Australia, Female, Humans, Alleles, Breast Neoplasms genetics, Genes, ras genetics, Minisatellite Repeats
- Published
- 2000
14. Modulated binding of SATB1, a matrix attachment region protein, to the AT-rich sequence flanking the major breakpoint region of BCL2.
- Author
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Ramakrishnan M, Liu WM, DiCroce PA, Posner A, Zheng J, Kohwi-Shigematsu T, and Krontiris TG
- Subjects
- Amino Acid Sequence, Animals, Base Pairing, Base Sequence, Breast Neoplasms, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, DNA-Binding Proteins chemistry, Exons, Female, Humans, Jurkat Cells, Lymphoma, Follicular genetics, Mice, Molecular Sequence Data, Nuclear Matrix metabolism, Peptide Fragments chemistry, Sequence Alignment, Sequence Homology, Amino Acid, Transfection, Translocation, Genetic, Tumor Cells, Cultured, DNA-Binding Proteins metabolism, Genes, bcl-2, Matrix Attachment Region Binding Proteins, Proto-Oncogene Proteins c-bcl-2 genetics
- Abstract
The t(14,18) chromosomal translocation that occurs in human follicular lymphoma constitutively activates the BCL2 gene and disrupts control of apoptosis. Interestingly, 70% of the t(14,18) translocations are confined to three 15-bp clusters positioned within a 150-bp region (major breakpoint region or [MBR]) in the untranslated portion of terminal exon 3. We analyzed DNA-protein interactions in the MBR, as these may play some role in targeting the translocation to this region. An 87-bp segment (87MBR) immediately 3' to breakpoint cluster 3 was essential for DNA-protein interaction monitored with mobility shift assays. We further delineated a core binding region within 87MBR: a 33-bp, very AT-rich sequence highly conserved between the human and mouse BCL2 gene (37MBR). We have purified and identified one of the core factors as the matrix attachment region (MAR) binding protein, SATB1, which is known to bind to AT-rich sequences with a high propensity to unwind. Additional factors in nuclear extracts, which we have not yet characterized further, increased SATB1 affinity for the 37MBR target four- to fivefold. Specific binding activity within 37MBR displayed cell cycle regulation in Jurkat T cells, while levels of SATB1 remained constant throughout the cell cycle. Finally, we demonstrated in vivo binding of SATB1 to the MBR, strongly suggesting the BCL2 major breakpoint region is a MAR. We discuss the potential consequences of our observations for both MBR fragility and regulatory function.
- Published
- 2000
- Full Text
- View/download PDF
15. The HRAS1 minisatellite locus and risk of ovarian cancer.
- Author
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Weitzel JN, Ding S, Larson GP, Nelson RA, Goodman A, Grendys EC, Ball HG, and Krontiris TG
- Subjects
- Alleles, Case-Control Studies, Chromosome Mapping, Female, Genes, BRCA1, Heterozygote, Humans, Middle Aged, Neoplasm Staging, Ovarian Neoplasms pathology, Proto-Oncogene Mas, Reference Values, Risk Factors, United States, White People genetics, Chromosomes, Human, Pair 11, Genes, ras, Minisatellite Repeats, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
- Abstract
Approximately 10% of ovarian cancers are due to mutations in highly penetrant inherited cancer susceptibility genes. The highly polymorphic HRAS1 minisatellite locus, located just downstream from the proto-oncogene H-ras-1 on chromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and bladder, and it was found that BRCAI mutation carriers with at least one rare HRAS1 allele have a greater risk of ovarian cancer than BRCA1 carriers with only common HRAS1 alleles. There are no conclusive studies of HRAS1 alleles in sporadic epithelial ovarian cancer. A case-control study of HRAS1 alleles was performed on DNA from 136 Caucasian patients with ovarian cancer and 108 cancer-free controls using conventional (Southern blot) and PCR-based methods to determine the frequency of rare HRAS1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression methods. A single degree of freedom test was used to assess the significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRAS1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated with a relative risk of 1.66 (95% CI, 0.91-3.01), whereas having two rare alleles increased the relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRAS1 allele types by the age of the case at diagnosis revealed that younger cases (<45 years) had a borderline statistically significant increased association with rare HRAS1 alleles compared to older cases (> or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRAS1 alleles contribute to ovarian cancer predisposition in the general population. Thus, the HRAS1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in both sporadic and hereditary ovarian cancer.
- Published
- 2000
16. Minisatellites and human disease.
- Author
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Krontiris TG
- Subjects
- Alleles, Consensus Sequence, DNA, Satellite metabolism, Gene Conversion, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Mutation, Transcription Factors metabolism, Transcriptional Activation, DNA, Satellite genetics, Diabetes Mellitus, Type 1 genetics, Minisatellite Repeats genetics, Neoplasms genetics
- Published
- 1995
- Full Text
- View/download PDF
17. Allelic variation of reporter gene activation by the HRAS1 minisatellite.
- Author
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Green M and Krontiris TG
- Subjects
- Adenovirus E1A Proteins genetics, Adenovirus E1A Proteins metabolism, Alleles, Avian Sarcoma Viruses genetics, Base Sequence, Binding Sites, Cell Line, Chloramphenicol O-Acetyltransferase genetics, Chloramphenicol O-Acetyltransferase metabolism, DNA, Satellite metabolism, Enhancer Elements, Genetic, Genes, Viral, Humans, Molecular Sequence Data, NF-kappa B metabolism, Oligodeoxyribonucleotides, Plasmids, Polymerase Chain Reaction, Repetitive Sequences, Nucleic Acid, Transcription, Genetic, Transcriptional Activation, Transfection, DNA, Satellite genetics, Gene Expression Regulation, Genes, ras
- Abstract
We have recently shown that constitutively expressed members of the rel/NF-kappa B family of transcription factors bind the HRAS1 minisatellite, VTRHRAS1. We now report that, like other NF-kappa B binding sites, VTRHRAS1 displays pleiotropic transcriptional regulatory activity that is promoter- and cell-type-specific. Both enhancement and suppression are restricted to the human bladder carcinoma cell line EJ, in which we have previously defined a unique form of NF-kappa B p50. We also observe allelic variation in functional activity: the rare a2.1 allele, one member of a class of HRAS1 alleles overrepresented in the genomes of cancer patients, possesses twofold greater enhancer activity than the low-risk alleles, a0.1, a1, and a2. Finally, VTRHRAS1 enhancer activity is upregulated by the adenovirus E1A 13S gene product, demonstrating the potential of the minisatellite for influencing gene expression through several distinct interactions with the transcriptional apparatus.
- Published
- 1993
- Full Text
- View/download PDF
18. IGH minisatellite suppression of USF-binding-site- and E mu-mediated transcriptional activation of the adenovirus major late promoter.
- Author
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Trepicchio WL and Krontiris TG
- Subjects
- Adenoviridae, Animals, Base Sequence, Cell Line, Enhancer Elements, Genetic, Humans, Mice, Models, Genetic, Molecular Sequence Data, Promoter Regions, Genetic, Suppression, Genetic, Transcription, Genetic physiology, Tumor Cells, Cultured, Upstream Stimulatory Factors, DNA, Satellite physiology, DNA-Binding Proteins metabolism, Genes, Immunoglobulin genetics, Transcription Factors metabolism
- Abstract
The 50bp repeat unit of the minisatellite within the DH-JH interval of the human immunoglobulin heavy chain locus binds a nuclear factor present in a wide variety of cell types. The binding site contains the myc/HLH motif, CACGTG, and represents a 15 of 17 base match for the USF/MLTF binding site adjacent to the adenovirus major late promoter (MLP). Unlike the USF/MLTF site, the IGH minisatellite possesses no enhancer activity. However, it can significantly suppress, in cis and in trans, USF-site-mediated transcriptional activation of the MLP. In murine myeloma cells, the IGH minisatellite can suppress, in trans, MLP activation by the murine heavy chain gene enhancer, E mu. These activities potentially represent a DNA-based form of squelching.
- Published
- 1993
- Full Text
- View/download PDF
19. The HRAS1 gene cluster: two upstream regions recognizing transcripts and a third encoding a gene with a leucine zipper domain.
- Author
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Weitzel JN, Kasperczyk A, Mohan C, and Krontiris TG
- Subjects
- Amino Acid Sequence, Base Sequence, Blotting, Southern, Cell Line, DNA, DNA Probes, GTP Phosphohydrolases genetics, Humans, Molecular Sequence Data, Restriction Mapping, Sequence Homology, Amino Acid, Transcription Factors genetics, Genes, ras, Leucine Zippers genetics, Multigene Family, Transcription, Genetic
- Abstract
We have cloned and characterized a 55-kb region of DNA surrounding HRAS1. It contains a cluster of two, and possibly three, genes associated with CpG islands within the 32 kb immediately upstream of HRAS1. We have sequenced cDNAs representing one of these genes, provisionally designated HRC1. The locus, which is located 29 kb upstream of HRAS1, is divergently transcribed. HRC1 cDNA probe recognizes fragments on Southern blots of DNA from other vertebrate species. In human DNA, multiple homologous fragments are detected in addition to the predicted ones containing HRC1. Therefore, this locus may represent a member of an evolutionarily conserved gene family. HRC1 expression is upregulated with HRAS1 in the EJ bladder carcinoma cell line, suggesting the possibility of coordinate regulation. The deduced translational product of the longest open reading frame (1119 nucleotides, 373 amino acids) predicts a protein with regions rich in glutamine and proline and a region similar to the helix-loop-helix motif adjacent to a carboxy-terminal leucine zipper dimerization motif with four heptad repeats. Alternate splicing of terminal exons occurs, resulting in the truncation of one proline-rich domain and preservation of the leucine zipper. Thus, a biologically important region of chromosome 11p consists of a gene cluster. At least one of these genes, in addition to HRAS1, may be involved in regulation of cell growth or differentiation.
- Published
- 1992
- Full Text
- View/download PDF
20. Members of the rel/NF-kappa B family of transcriptional regulatory proteins bind the HRAS1 minisatellite DNA sequence.
- Author
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Trepicchio WL and Krontiris TG
- Subjects
- Base Sequence, Binding Sites genetics, Gene Expression Regulation genetics, Humans, Molecular Sequence Data, Oligodeoxyribonucleotides genetics, Oligodeoxyribonucleotides metabolism, Proto-Oncogene Proteins c-rel, Tumor Cells, Cultured, DNA, Satellite metabolism, Genes, ras genetics, NF-kappa B metabolism, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins metabolism, Repetitive Sequences, Nucleic Acid genetics
- Abstract
The 28 base pair repeat unit of a minisatellite 1000 bp downstream from the human HRAS1 gene (VTRHRAS1) bound four proteins (p45, p50, p72 and p85) in nuclear extracts from a variety of human cell lines which were indistinguishable from several members of the rel/NF-kappa B family of transcriptional regulatory factors. VTRHRAS1 bound the constitutively expressed, but not the inducible, forms of these proteins. Analysis of partially purified binding factors from different cell lines demonstrated qualitative differences in the p50 subunit; phosphocellulose fractionation also revealed considerable heterogeneity in the p72 and p85 subunits. These results suggest the possibility that the HRAS1 minisatellite, in serving as a tandem array of rel/NF-kappa B binding sites, may function in the transcriptional regulation of HRAS1 and nearby genes.
- Published
- 1992
- Full Text
- View/download PDF
21. Minisatellite allele diversification: the origin of rare alleles at the HRAS1 locus.
- Author
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Kasperczyk A, DiMartino NA, and Krontiris TG
- Subjects
- Exons, Genetic Markers, Humans, Multigene Family, Polymorphism, Genetic, Promoter Regions, Genetic, Repetitive Sequences, Nucleic Acid, Restriction Mapping, Alleles, DNA, Satellite, Genes, ras
- Abstract
Three genetic markers within the promoter-exon 1 region of the HRAS1 locus have been employed to investigate lineage relationships among alleles of the highly polymorphic variable tandem repeat (VTR) immediately downstream of the HRAS1 gene. These markers were in absolute linkage disequilibrium with the HRAS1 VTR, allowing the assignment of unique upstream haplotypes to each of the four common VTR alleles. Analysis of 17 rare alleles revealed a stratification of allele fragment size and upstream haplotype in which each rare VTR allele possessed the markers characteristic of the common allele nearest in size. Therefore, hyperallelism emanated from the four common alleles in a defined fashion, the size of a rare allele specifying its origin. As discussed below, this result implies that unequal crossing-over between homologues is unlikely to be the predominant mechanism for generating new VTR alleles at this minisatellite locus.
- Published
- 1990
22. Association of rare alleles of the Harvey ras protooncogene locus with lung cancer.
- Author
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Sugimura H, Caporaso NE, Modali RV, Hoover RN, Resau JH, Trump BF, Longergan JA, Krontiris TG, Mann DL, and Weston A
- Subjects
- Adenocarcinoma genetics, Case-Control Studies, Cells, Cultured, DNA genetics, DNA, Neoplasm genetics, Gene Frequency, Humans, Lung Diseases, Obstructive genetics, Lymphocytes pathology, Alleles, Genes, ras, Lung Neoplasms genetics
- Abstract
The hypothesis that rare variable nucleotide tandem repeat alleles of the Ha-ras-1 polymorphism are an inherited predisposing factor in human lung carcinogenesis has been evaluated in an age, race, and smoking matched case-control study. Twenty-three different alleles were identified by their restriction fragment length in DNA isolated from peripheral blood lymphocytes and were categorized into three groups: common; intermediate; and rare. The frequencies of rare alleles in blacks with either squamous cell carcinoma, large cell carcinoma, or small cell carcinoma were found to be significantly higher than those among groups of control subjects that were comprised of chronic obstructive pulmonary disease patients and patients with cancer at sites other than the lung. A similar trend which did not reach statistical significance was observed in whites. These data are consistent with the hypothesis that inheritance of Ha-ras-1 rare restriction fragment length alleles represents a genetic risk factor for some human lung cancers. The biological basis of this observation remains to be clarified, and it is possible that ethnic variations in rare allele frequencies are responsible for the differences noted. However, the data suggest that further evaluation of the Ha-ras-1 polymorphism as a marker of individual lung cancer susceptibility is warranted.
- Published
- 1990
23. The human minisatellite consensus at breakpoints of oncogene translocations.
- Author
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Krowczynska AM, Rudders RA, and Krontiris TG
- Subjects
- Base Sequence, DNA Nucleotidyltransferases genetics, Gene Rearrangement, Humans, Molecular Sequence Data, Polymorphism, Restriction Fragment Length, Repetitive Sequences, Nucleic Acid, Sequence Homology, Nucleic Acid, Tumor Cells, Cultured, VDJ Recombinases, DNA, Satellite genetics, Immunoglobulin Heavy Chains genetics, Oncogenes, Recombination, Genetic, Translocation, Genetic genetics
- Abstract
A reexamination of human minisatellite (hypervariable) regions following the cloning and sequencing of the new minisatellite, VTR1.1, revealed that many of these structures possessed a strongly conserved copy of the chi-like octamer, GC[A/T]GG[A/T]GG. In oncogene translocations apparently created by aberrant VDJ recombinase activity, this VTR octamer was often found within a few bases of the breakpoint (p less than 10(-10)). Three bcl2 rearrangements which occurred within 2 bp of one another were located precisely adjacent to this consensus; it defined the 5' border of that oncogene's major breakpoint cluster. Several c-myc translocations also occurred within 2 bp of this sequence. While the appearance of a chi-like element in polymorphic minisatellite sequences is consistent with a role promoting either recombination or replication slippage, the existence of such elements at sites of somatic translocations suggests chi function in site-specific recombination, perhaps as a subsidiary recognition signal in immunoglobulin gene rearrangement. We discuss the implications of these observations for mechanisms by which oncogene translocations and minisatellite sequences are generated.
- Published
- 1990
- Full Text
- View/download PDF
24. A variable tandem repeat locus mapped to chromosome band 10q26 is amplified and rearranged in leukocyte DNAs of two cancer patients.
- Author
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Colb M, Yang-Feng T, Francke U, Mermer B, Parkinson DR, and Krontiris TG
- Subjects
- Base Sequence, Colonic Neoplasms genetics, DNA Restriction Enzymes, Gene Amplification, Humans, Leukocytes physiology, Rectal Neoplasms genetics, Urinary Bladder Neoplasms genetics, Chromosomes, Human, Pair 10, DNA, Neoplasm genetics, DNA, Satellite genetics, Repetitive Sequences, Nucleic Acid
- Abstract
A highly polymorphic locus associated with the variable tandem repetition of a 35 bp consensus sequence was mapped to chromosome 10, band q26. Examination of leukocyte DNA from a cancer patient revealed the twenty-fold amplification of one allelic fragment of this locus, while the other allelic fragment demonstrated a normal copy number. In another patient, Southern blotting of leukocyte DNA detected the deletion of the 3'-flanking region from one tandem repeat allele. These results indicate that variable tandem repeats may mark highly unstable regions of DNA in the human genome which can be altered by changes more extensive than simple tandem repeat variation.
- Published
- 1986
- Full Text
- View/download PDF
25. Unique allelic restriction fragments of the human Ha-ras locus in leukocyte and tumour DNAs of cancer patients.
- Author
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Krontiris TG, DiMartino NA, Colb M, and Parkinson DR
- Subjects
- Cell Line, DNA Restriction Enzymes metabolism, Deoxyribonuclease BamHI, Deoxyribonuclease HpaII, Female, Genotype, Humans, Leukocytes analysis, Neoplasms genetics, Polymorphism, Genetic, Alleles, Chromosome Mapping, DNA analysis, DNA, Neoplasm analysis
- Abstract
White blood cell DNA from cancer patients and DNA from tumours and tumour-derived cell lines frequently demonstrated allelic restriction fragments of the Harvey ras oncogene locus not found in the unaffected population. The presence of such unusual alleles may be linked to susceptibility to cancer.
- Published
- 1985
- Full Text
- View/download PDF
26. Allele-specific deletion in exon I of the HRAS1 gene.
- Author
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Kasperczyk A, Mermer BA, Parkinson DR, Lonergan JA, and Krontiris TG
- Subjects
- Alleles, Base Sequence, Exons, Gene Frequency, Humans, Molecular Sequence Data, Polymorphism, Restriction Fragment Length, RNA Probes, Chromosome Deletion, Genes, ras, Melanoma genetics, Oncogene Protein p21(ras) genetics
- Abstract
We have detected a 6-bp deletion in the untranslated first exon of a unique HRAS1 gene cloned from lymphocyte DNA of a familial melanoma patient. The deletion is without apparent functional consequence. Using an RNase protection assay, we have demonstrated the deletion in leukocyte DNAs of individuals unrelated to the patient. In these cases, the deletion marker is specifically associated with one class of common HRAS1 allele, thereby establishing the origin of the unique allele. We discuss the means by which DNA sequence heterogeneity at other loci may be rapidly analyzed.
- Published
- 1989
27. Clonal analysis of untreated non-Hodgkin's lymphoma utilizing immunoglobulin gene rearrangement and immunophenotype.
- Author
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Rudders RA, Dhillon S, and Krontiris TG
- Subjects
- B-Lymphocytes immunology, Cell Differentiation, Genetic Variation, Genotype, Humans, Lymphoma, Non-Hodgkin genetics, Phenotype, Gene Rearrangement, Genes, Immunoglobulin, Lymphoma, Non-Hodgkin immunology, Neoplastic Stem Cells immunology
- Abstract
We have prospectively examined 66 consecutive initial diagnostic lymph node biopsies from unselected patients suspected of having malignant lymphoma for clonal immunophenotypic and immunogenotypic markers. By morphological and cell surface phenotypic criteria 52 had non-Hodgkin's lymphoma derived from the B-cell lineage and in these we compared surface immunoglobulin criteria for clonality with immunoglobulin gene rearrangement as detected by JH, C kappa, and C lambda gene probes. We found that the addition of BglII and HindIII double digests to the standard BamHI and EcoRI restriction enzymes made it possible to detect rearrangement in the vast majority of lymphomas and that rearrangement of both JH alleles is the rule. A rearranged heavy and/or light chain gene was detected in 47 of 52 (91%) tumors and the JH probe alone detected rearrangements in 87% of tumors when multiple restriction enzymes were used. In contrast, surface immunoglobulin, the standard clonal marker for monoclonal B-cell malignancy, was either undetectable or did not exhibit light chain restriction in 29 of 52 tumors as detected by flow cytometric analysis. Further, in 24 of these 29 tumor DNAs we could detect an Ig gene rearrangement. In follicular (nodular) lymphoma which often gives ambiguous immunophenotypic results by cell suspension techniques, monoclonal gene rearrangements were detected in 16 of 18 tumor DNAs. Monoclonal surface immunoglobulin was detected in only 8 of 18 of this subset of cases. The 52 tumors were also analyzed for potential oligoclonality. We found that the use of BglII, a restriction enzyme that closely spanned the JH region, increased the sensitivity of detecting rearrangements and facilitated the identification of isotype switch variants. In only a single (1 of 52) tumor DNA were more than two rearranged bands seen with JH, C kappa, and C lambda probes, suggesting a multiclonal origin. Additional cases thought to potentially represent oligoclonality by immunophenotypic criteria proved to be isotype switch variants. We conclude that Ig gene rearrangement is an extremely sensitive method for defining monoclonality in lymphoma cell populations, particularly if multiple restriction enzymes are used, and that the vast majority of the clonal diversity seen in initial diagnostic biopsies is the result of isotypic switch within a given clone rather than true oligoclonality.
- Published
- 1988
28. Host restriction of Friend leukemia virus. Role of the viral outer coat.
- Author
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Krontiris TG, Soeiro R, and Fields BN
- Subjects
- Animals, Cell Line, Embryo, Mammalian, Friend murine leukemia virus drug effects, Immune Sera pharmacology, Mice, Mice, Inbred BALB C, Phenotype, Vesicular stomatitis Indiana virus drug effects, Viral Plaque Assay, Friend murine leukemia virus growth & development, Genes, Viral Proteins, Virus Replication
- Abstract
Host restriction of oncogenesis of RNA tumor viruses in vivo is associated with several gene loci. One of these genes, the Fv-1 locus in mice, is expressed in vitro and may be studied in mouse-embryo cultures that are restrictive or permissive for replication of Friend leukemia virus. Two strains of Friend leukemia virus, N-or B-tropic, show reciprocal ability to replicate successfully in either NIH Swiss (N-type) or BALB/c (B-type) cells that differ at the Fv-1 locus. These two strains of virus and two cell lines form a system to measure host restriction in vitro. Measurement of adsorption of Friend leukemia virus to permissive or restrictive cells reveals no difference in rate or total amount of virus bound. Furthermore, studies with virions of vesicular stomatitis virus phenotypically mixed within an envelope containing Friend leukemia virus protein show no differences in penetration or replication of vesicular stomatitis virus. These results strongly suggest that host restriction of Friend leukemia virus is due to an intracellular event in the viral replication cycle.
- Published
- 1973
- Full Text
- View/download PDF
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