Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We detected telomerase activity in human lymphocytes obtained from normal donors. Telomerase was up-regulated within 24 h when peripheral blood mononuclear cells were cultured in the presence of phytohemagglutinin. The activity increased gradually over 72 h, then remained stable for 96 h. During this period, cell number and the length of telomeric DNA remained constant. Anti-CD3 monoclonal antibody and Pansolbin also induced telomerase activity. These results demonstrate that telomerase is regulated during lymphocyte activation as cells progress from G0 to S phase. This system is useful for the study of telomerase during carcinogenesis, and in the testing of telomerase-inhibitory drugs.
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PMID:Up-regulation of telomerase activity in human lymphocytes. 898 80

Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in addition to their chemical properties, the estrogenic property of these compounds allows them to act like sex hormones. Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like chemicals are known to produce adverse effects. The source of extra or elevated concentration of estrogen could be either endogenous or exogenous. The potential of exposure for humans and animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds, such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental estrogen-like chemicals produce multiple and multitype genetic and/or nongenetic hits. Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-1 receptor, is altered; and (4) DNA repair gene DNA polymerase beta transcripts are decreased and mutated. Exposure of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may also follow a similar pattern of effects to DES, because we have recently shown that these compounds alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like chemical. The role of individual attack leading to a particular change is not clear at this stage. Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death; (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as unstable cells. Proliferation of the last type of cell is expected to result in transformed cells.
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PMID:Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals. 901 29

Loss of heterozygosity (LOH) on chromosome 17 is a frequent genetic alteration in breast cancer. To assess whether the location of potential tumor suppressor genes is compatible with the LOH pattern in individual tumors, we analyzed allele loss on chromosome 17 in 121 invasive ductal breast carcinomas and 16 benign breast tumors with 14 polymorphic microsatellite markers (4 on 17p and 10 on 17q). Fluorescent polymerase chain reaction (PCR) for typing microsatellites coupled with DNA fragment analysis in an automated DNA sequencer was applied. Frequencies of LOH varied from 29.4% (D17S1322) to 57.4% (TP53-Alu). No LOH could be detected in benign breast tumors. In 54 tumors the deletion patterns were consistent with the complete loss of 17p (n = 28), 17q (n = 9) or the whole chromosome 17 (n = 17). Five smallest regions of overlap (SROs) were identified in tumors with interstial deletion patterns. On 17p, two foci were detected affecting the TP53 locus and the hypermethylated in cancer I (HICI) region (17p13.3). On 17q, SRO1 was localized between markers THRAI and D17S855, centromeric to the breast/ovarian cancer gene BRCAI; SRO2 was flanked by markers AFM234 and NMEI, and SRO3 was centered between markers MPO and GH. Associations between LOH and histopathological characteristics were determined. Significant correlations were found between higher grade and loss of the TP53 gene (marker TP53, P = 0.019), loss of the BRCAI region (P < 0.009), LOH of marker AFM155 (P = 0.003) and marker NMEI (P = 0.026). For positive estrogen receptor status, only LOH of the THRAI marker correlated significantly, whereas highly significant correlations were determined between positive progesterone receptor and markers centromeric to the BRCAI region D17S250 (P = 0.00002), THRAI (P = 0.0006), and the intragenic BRCAI markers [D17S1322 (P = 0.021), D17S855 (P = 0.029)]. Results presented in this study identify five independent regions of chromosome 17 which are likely to contain potential tumor suppressor genes involved in the carcinogenesis of sporadic breast cancer.
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PMID:Patterns of allelic loss on chromosome 17 in sporadic breast carcinomas detected by fluorescent-labeled microsatellite analysis. 907 71

Benzene is a well-characterized human carcinogen and clastogen still present in both the occupational and general environment. However, the levels of benzene encountered today are, in most cases, relatively low and new methods, more specific and sensitive than classical cytogenetics, are probably needed to assess if current benzene exposures pose a genotoxic risk to human health. Bearing in mind the leukaemogenic action of benzene, blood lymphocytes appear to be a suitable cell system for biomonitoring studies. Buccal epithelium is an alternative source of tissue for monitoring human exposure to inhaled occupational and environmental genotoxicants. New molecular cytogenetic techniques allowing us to specifically study clastogenic or aneugenic events in human cells may provide the additional sensitivity required. In the present study, fluorescence in situ hybridization was used to examine the content of micronuclei (MN) (using the pan-centromeric DNA probe SO-alphaAllCen) in lymphocytes and buccal cells and to detect numerical abnormalities of chromosome 9 (using a chromosome 9 centromere-specific alphoid DNA probe) in buccal cells from a population occupationally exposed to benzene in an Estonian petrochemical plant. Age-matched Estonian volunteers were used as a control group. Individual benzene exposure levels were estimated to be around 1 p.p.m. (8 h time-weighted average). No increases in the frequency of total MN, MN harbouring whole chromosomes or acentric chromosomal fragments or chromosome 9 numerical abnormalities were detected in relation to benzene exposure in the present study. The lack of positive results was consistent in both buccal cells and lymphocytes, indicating that the benzene exposure levels encountered did not induce detectable clastogenic or aneugenic effects in the exposed workers. Other variables and confounding factors, such as age, smoking or alcohol consumption, did not influence any of the multiple cytogenetic biomarkers analysed.
Carcinogenesis 1997 Apr
PMID:Molecular cytogenetic analysis of buccal cells and lymphocytes from benzene-exposed workers. 911 Dec 20

Tumor tissue samples were obtained from each of ten patients with stomach cancer who had undergone surgery. The simultaneous detection of signals from 17 alpha pericentromeric and 17 p 13.1 loci after hybridization with the appropriate probes was carried out on 100-200 tumor cells in each case. The copy number category (i.e., monosomy, disomy, trisomy, and so on) was defined as described by Waldman et al., and the deletion of a gene of interest was defined as described by Matsumura et al. The copy number category was monosomic in seven and disomic in three out of ten cases. The frequency of the copy number 2 (two centromeric signals per nucleus) was lower in tumor cells than in control cells that comprise normal gastric epithelium cells and cells from a normal fibroblast cell line. The copy numbers 3, 4, 5, and above (polysomy) were more frequent in tumor cells, whereas no normal cells having three or more centromeric signals per nucleus was present in the control. Incidence of p 53 gene deletion in ten patients ranged from 55.4% to 90.0%, and from 1.5% to 30.7% if nuclei having three or more copy numbers were taken into consideration. The mean incidence of the p 53 deletion was significantly higher in the differentiated type than in the undifferentiated type of carcinoma (p < 0.02). Various types in the combination pattern of 17 alpha centromere/17 p 13.1 signals were observed, and the most frequent pattern in the ten cases was a combination of 1/1. The deletion of chromosome 17 p may play an important role in carcinogenesis of the stomach.
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PMID:Chromosome 17 copy numbers and incidence of p 53 gene deletion in gastric cancer cells. Dual color fluorescence in situ hybridization analysis. 911 49

In a human fibroblast clone we studied the evolution, during culture propagation, of a dicentric chromosome consisting of the end-to-end association of the short arm of chromosome 5 and the long arm of chromosome 16. Dual-color fluorescence in situ hybridization (FISH) with painting probes allowed us to define the structure of a variety of derivative chromosomes and to identify the mechanisms by which they originated. Asymmetric interchanges involving the intercentromeric region of the dicentric, bridge-breakage-fusion events, or breaks followed by sister chromatid fusion, originate unstable hetero- or homodicentric chromosomes with deletion or duplication; breakages not followed by reunion, or intradicentric recombination, presumably originate stable rearranged monocentric chromosomes. The variety of the derivatives is extremely large because the observed events may involve any site of the intercentromeric region, although the majority of them occurs after a break in 16qh. The results of this investigation document the evolution through successive steps of a telomeric fusion, a chromosome anomaly frequently observed in tumor and senescent cells. They also demonstrate that in cultured cells of normal origin, starting with this anomaly, various chromosomal mechanisms may produce translocations, duplications, and deletions. The karyotype instability produced by a telomeric fusion can be relevant for carcinogenesis because it may generate genetic changes critical in the multistep process of transformation.
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PMID:Telomeric fusions in cultured human fibroblasts as a source of genomic instability. 916 29

Recent studies have demonstrated a strong association between carcinogenesis and re-activation of telomerase in various human tumors. In the present study, we have analyzed the telomerase activity in 105 oral mucosal samples, including normal mucosa and premalignant and malignant lesions, by using the telomeric repeat amplification protocol assay. The telomerase activity was detected in normal oral squamous epithelium and in 75% of the oral leukoplakias and oral carcinomas. Although the telomerase activity was observed in normal and hyperplastic squamous epithelium, it showed some relationship with certain clinico-pathological factors in malignant lesions. Telomerase activity was found to have a relationship with the grade of tumor differentiation. Of 34 well-differentiated squamous cell carcinomas, only 10 (30%) exhibited high telomerase activity, whereas in moderately or poorly differentiated squamous cell carcinomas, all seven (100%) tumors displayed high activity. In addition, the level of telomerase activity had an inverse correlation with the treatment response in the early-stage tumors, and the activity differed significantly between the tumors in the following intraoral sites: nonkeratinizing mucosa (buccal mucosa, alveolus, and floor of mouth) and tongue. This preliminary result shows that telomerase activity is present in normal oral squamous epithelium, as it is in normal hematopoietic cells and in carcinomas, and that telomerase activity has a relationship with degree of tumor differentiation and treatment response. Thus, assessing the telomerase activity may be a useful prognostic marker in oral squamous cell carcinomas.
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PMID:Telomerase activity in premalignant and malignant lesions of human oral mucosa. 918 74

Accumulating evidence indicates that telomerase activity is stringently repressed in normal human somatic cells but reactivated in cancers and immortal cells, suggesting that activation of telomerase activity may play a role in carcinogenesis and immortalization. Recently, down-regulation of telomerase activity by induction of differentiation has been reported for cells of pre-myelocytic and myelocytic leukemia as well as embryonic carcinoma. To gain further insight about the regulation of telomerase activity following induction of differentiation, telomerase activity was examined in a human hematopoietic progenitor cell line (D2), a melanoma cell line (CM73-36) and a glioma cell line (Ast812) before and after addition of differentiation inducing agents. The state of differentiation was assessed by growth inhibition and cell morphological maturation. Telomerase activity was assayed by a PCR-based telomeric repeat amplification protocol (TRAP). Our data show that telomerase activity was inhibited only in differentiation-induced D2 cells but not in differentiation-induced melanoma and glioma cells. A model for the differential inhibition of telomerase activity following induction of differentiation in different cancer cells will be presented.
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PMID:Differential inhibition of telomerase activity during induction of differentiation in hematopoietic, melanoma, and glioma cells in culture. 926 30

Telomeres, the protein-DNA complexes that comprise the ends of linear eukaryotic chromosomes, serve to protect the chromosome ends and allow their complete replication. Telomeres also appear to play an essential role in chromosome segregation. In most organisms telomeric DNA consists of a series of short repeats that are variable in length, but regulated at a fixed average value in the germline. The possible involvement of telomere repeat shortening in aging and carcinogenesis has recently attracted attention to the more basic question of how telomere length is sensed and regulated by the cell. Telomere length in the budding yeast Saccharomyces cerevisiae has been known for over a decade now to be under complex genetic control, and this organism has provided a useful model system to address basic mechanistic questions. This review focuses on recent studies in yeast which indicate that the double-strand telomere-repeat binding protein Rap1 may play an important role in a negative-feedback mechanism that senses and controls the length of the telomere repeats. Although the same carboxy-terminal domain of Rap1p is involved in both telomere length regulation and telomeric silencing (telomere position effect), it appears that these two functions are mediated by separate sets of Rap1p-interacting proteins. Results from other systems suggest that negative regulation of telomere elongation by a double-stranded telomere-repeat binding protein may be a highly conserved strategy for telomere length control.
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PMID:Telomere length regulation: getting the measure of chromosome ends. 927 38

Small mutations, megabase deletions, and aneuploidy are involved in carcinogenesis and genetic defects, so it is important to be able to quantify these mutations and understand mechanisms of their creation. We have previously quantified a spectrum of mutations, including megabase deletions, in human chromosome 11, the sole human chromosome in a hamster-human hybrid cell line AL. S1- mutants have lost expression of a human cell surface antigen, S1, which is encoded by the M1C1 gene at 11p13 so that mutants can be detected via a complement-mediated cytotoxicity assay in which S1+ cells are killed and S1- cells survive. But loss of genes located on the tip of the short arm of 11 (11p15.5) is lethal to the AL hybrid, so that mutants that have lost the entire chromosome 11 die and escape detection. To circumvent this, we fused AL with Chinese hamster ovary (CHO) cells to produce a new hybrid, ALC, in which the requirement for maintaining 11p15.5 is relieved, allowing us to detect mutations events involving loss of 11p15.5. We evaluated the usefulness of this hybrid by conducting mutagenesis studies with colcemid, 137Cs gamma-radiation and UV 254 nm light. Colcemid induced 1000 more S1- mutants per unit dose in ALC than in AL; the increase for UV 254 nm light was only two-fold; and the increase for 137Cs gamma-rays was 12-fold. The increase in S1- mutant fraction in ALC cells treated with colcemid and 137Cs gamma-rays were largely due to chromosome loss and 11p deletions often containing a breakpoint within the centromeric region.
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PMID:Chromosomal mutations and chromosome loss measured in a new human-hamster hybrid cell line, ALC: studies with colcemid, ultraviolet irradiation, and 137Cs gamma-rays. 935 44


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