Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of DNA polymerase beta (polbeta), an error-prone DNA repair enzyme, has been shown to result in mutagenesis, aneuploidy and tumorigenesis. To further investigate the molecular basis leading to cancer-associated genetic changes, we examined whether the DNA polbeta could affect homologous recombination (HR). Using mammalian cells carrying an intrachromosomal recombination marker we showed that the DNA polbeta overexpression increased the HR mostly by enhancing gene conversion. Concomitantly, we observed the generation of DNA strand breaks as well as a DNA polbeta-dependent formation of Rad51 foci. The stimulation of HR was abolished by the coexpression of a dominant negative form of Rad51, suggesting that the Rad51 was involved in the increased HR events. The expression of different DNA polbeta mutants lacking polymerase activity did not result in HR stimulation, indicating that the DNA synthesis activity of DNA polbeta was related to this phenotype. These results provide new insights into the molecular mechanisms of the genetic instability observed in DNA polbeta overexpressing tumour cells.
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PMID:DNA polymerase beta overexpression stimulates the Rad51-dependent homologous recombination in mammalian cells. 1545 77

Telomeres are nucleoprotein complexes that cap the end of eukaryotic chromosomes. They are essential for the functions and the stability of the genomes. There is now compelling evidences that telomerase, the enzyme that adds telomeric DNA repeats to chromosome end, is an important player in oncogenesis. The absence of telomerase in somatic tissues is thought to promote genome instability at initial stages of oncogenesis, favoring the emergence of cancer-associated chromosomal abnormalities \; restablishment of telomerase activity is expected afterwards if long term cell cycling is to occur. In addition to telomerase, various factors control the structure and function of telomeres, suggesting that additional telomeric components play important roles during oncogenesis.
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PMID:[Telomere and cancer: what's more at the end?]. 1563 18

Phosphatidylinositol 3-kinase (PI3-kinase) is a novel intracellular transducer involved in a wide range of cancer-associated signaling pathways, which comprises various isoforms and splice variants with distinct biologic activities and clinical implications. Especially, the class Ia PI3-kinase 110 kD catalytic subunit alpha (PIK3CA) is the most important isoform in tumorigenesis and possibly, tumor angiogenesis. Several strategies have been developed to block PI3-kinase for cancer therapy; however, the approach to target specific PI3-kinase isoform has not been explored to date. In the present study, we show that RNA interference (RNAi) through small interfering (siRNA) sequences targeting PIK3CA has potential applications in isoform-specific "knock-down" of PI3-kinase. This strategy provides a novel tool to study the function of various PI3-kinase isoforms and may contribute to isoform-specific targeting of PI3-kinase in human cancer.
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PMID:RNA interference: a potential strategy for isoform-specific phosphatidylinositol 3-kinase targeted therapy in ovarian cancer. 1566 37

Our previous studies have defined reactive stroma in human prostate cancer and have developed the differential reactive stroma (DRS) xenograft model to evaluate mechanisms of how reactive stroma promotes carcinoma tumorigenesis. Analysis of several normal human prostate stromal cell lines in the DRS model showed that some rapidly promoted LNCaP prostate carcinoma cell tumorigenesis and others had no effect. These differential effects were due, in part, to elevated angiogenesis and were transforming growth factor (TGF)-beta1 mediated. The present study was conducted to identify and evaluate candidate genes expressed in prostate stromal cells responsible for this differential tumor-promoting activity. Differential cDNA microarray analyses showed that connective tissue growth factor (CTGF) was expressed at low levels in nontumor-promoting prostate stromal cells and was constitutively expressed in tumor-promoting prostate stromal cells. TGF-beta1 stimulated CTGF message expression in nontumor-promoting prostate stromal cells. To evaluate the role of stromal-expressed CTGF in tumor progression, either engineered mouse prostate stromal fibroblasts expressing retroviral-introduced CTGF or 3T3 fibroblasts engineered with mifepristone-regulated CTGF were combined with LNCaP human prostate cancer cells in the DRS xenograft tumor model under different extracellular matrix conditions. Expression of CTGF in tumor-reactive stroma induced significant increases in microvessel density and xenograft tumor growth under several conditions tested. These data suggest that CTGF is a downstream mediator of TGF-beta1 action in cancer-associated reactive stroma and is likely to be one of the key regulators of angiogenesis in the tumor-reactive stromal microenvironment.
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PMID:Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. 1620 60

Gene deregulation is a frequent cause of malignant transformation. Alteration of the gene structure and/or expression leading to cellular transformation and tumor growth can be experimentally achieved by insertion of the retroviral genome into the host DNA. Retrovirus-containing host loci found repeatedly in clonal tumors are called common viral integration sites (cVIS). cVIS are located in genes or chromosomal regions whose alterations participate in cellular transformation. Here, we present the chicken model for the identification of oncogenes and tumor suppressor genes in solid tumors by mapping the cVIS. Using the combination of inverse PCR and long terminal repeat-rapid amplification of cDNA ends technique, we have analyzed 93 myeloblastosis-associated virus type 2-induced clonal nephroblastoma tumors in detail, and mapped >500 independent retroviral integration sites. Eighteen genomic loci were hit repeatedly and thus classified as cVIS, five of these genomic loci have previously been shown to be involved in malignant transformation of different human cell types. The expression levels of selected genes and their human orthologues have been assayed in chicken and selected human renal tumor samples, and their possible correlation with tumor development, has been suggested. We have found that genes associated with cVIS are frequently, but not in all cases, deregulated at the mRNA level as a result of proviral integration. Furthermore, the deregulation of their human orthologues has been observed in the samples of human pediatric renal tumors. Thus, the avian nephroblastoma is a valid source of cancer-associated genes. Moreover, the results bring deeper insight into the molecular background of tumorigenesis in distant species.
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PMID:Identification of potential human oncogenes by mapping the common viral integration sites in avian nephroblastoma. 1639 19

Expression of Breast Cancer Resistance Protein (BCRP/ABCG2) in tumor cells is associated with resistance to multiple chemotherapeutic agents. BCRP also protects against phototoxicity by mediating the efflux of protoporphyrins from cells. However, chemotherapy and photodynamic therapy are effective treatment options for cancer. Furthermore, protoporphyrins are essential, in the form of heme, for the synthesis of nitric oxide, over-production of which is associated with cancer. This raises the question as to whether the expression of this transporter is altered in cancer. To address this question, we investigated the expression of BCRP in colorectal cancer and cervical cancer. Paired normal and cancer tissues from colectomy specimens were used for the analysis of BCRP mRNA by RT-PCR and Northern blot. BCRP was analyzed by immunohistochemistry/immunofluorescence. Similar studies were also done with specimens of normal cervix and cancer cervix. A commercial dot blot was probed to quantify the expression of BCRP in paired normal and cancer cDNA samples from 154 patients with tumors in 19 different tissues. BCRP mRNA was present in normal colorectal tissue and showed a 6-fold decrease in cancer. BCRP was abundant in the normal colon and showed a decrease in colon cancer. The down-regulation of BCRP mRNA and protein was also evident in cervical cancer. There was also a decrease in BCRP mRNA in cancer in 12 of the 19 different tissues collected from 154 patients. These data show that cancer-associated down-regulation of BCRP is likely to be a common phenomenon in several tissues. Decreased expression of BCRP may have a role in tumorigenesis by allowing accumulation of genotoxins and over-production of nitric oxide.
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PMID:Down-regulation of BCRP/ABCG2 in colorectal and cervical cancer. 1655 28

The role of infectious agents in the development of cancer is well-established. For example, numerous RNA and DNA viruses express dedicated oncoproteins that are able to transform cells in vitro and induce rapid tumor formation in experimental animals. Curiously, these acutely-transforming viruses are seldom associated with naturally occurring neoplasms of humans or animals. Conversely, the microbial pathogens that are linked to cancers in natural hosts rarely encode acutely transforming proteins. Moreover, they tend to down-regulate most of their genes except for genes affecting cell survival, often via the NF-kappaB pathway. This allows the pre-neoplastic cell to avoid triggering cytotoxic immunity and the ensuing acute inflammation. These host responses not only kill tumor cells directly, but also strongly suppress the development of new blood vessels (neovascularization), which is absolutely essential for neoplastic growth. Chronic inflammation, on the other hand, promotes neoplastic cell growth and may even be conducive to neovascularization. Thus, cancer-associated microbial pathogens must follow the "less is more" principle. According to this principle, only minor perturbations in cell proliferation and death are tolerated by the host, but in the long run, they are all that is necessary for tumorigenesis.
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PMID:Infection & neoplastic growth 101: the required reading for microbial pathogens aspiring to cause cancer. 1661 Jul 8

Helicobacter pylori produces acute superficial gastritis in nearly all of its human hosts. However, a subset of individuals develops chronic atrophic gastritis (ChAG), a condition characterized in part by diminished numbers of acid-producing parietal cells and increased risk for development of gastric adenocarcinoma. Previously, we used a gnotobiotic transgenic mouse model with an engineered ablation of parietal cells to show that loss of parietal cells provides an opportunity for a H. pylori isolate from a patient with ChAG (HPAG1) to bind to, enter, and persist within gastric stem cells. This finding raises the question of how ChAG influences H. pylori genome evolution, physiology, and tumorigenesis. Here we describe the 1,596,366-bp HPAG1 genome. Custom HPAG1 Affymetrix GeneChips, representing 99.6% of its predicted ORFs, were used for whole-genome genotyping of additional H. pylori ChAG isolates obtained from Swedish patients enrolled in a case-control study of gastric cancer, as well as ChAG- and cancer-associated isolates from an individual who progressed from ChAG to gastric adenocarcinoma. The results reveal a shared gene signature among ChAG strains, as well as genes that may have been lost or gained during progression to adenocarcinoma. Whole-genome transcriptional profiling of HPAG1's response to acid during in vitro growth indicates that genes encoding components of metal uptake and utilization pathways, outer membrane proteins, and virulence factors are among those associated with H. pylori's adaptation to ChAG.
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PMID:The complete genome sequence of a chronic atrophic gastritis Helicobacter pylori strain: evolution during disease progression. 1678 65

This study evaluated possible effects of radiofrequency (RF) radiation on tumorigenesis induced by the mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) given in drinking water. Female Wistar rats aged 7 weeks at the beginning of the experiments were randomly divided into four groups of 72 animals: a cage-control group and three MX-exposed groups (a daily average dose of 1.7 mg MX/kg body weight for 104 weeks), of which two were exposed to 900 MHz pulsed RF radiation and the third served as a sham-RF-radiation group. The RF-radiation groups were exposed 2 h per day, 5 days per week for 104 weeks at nominal whole-body average SARs of 0.3 W/kg and 0.9 W/kg. Complete histopathology was performed on the rats of the three MX-exposed groups. The tumor types and incidences observed in the MX-exposed animals were similar to those reported earlier in MX-exposed female Wistar rats. RF radiation did not statistically significantly affect mortality or organ-specific incidence of any tumor type. The only statistically significant difference was an increase in the combined frequency of vascular tumors of the mesenteric lymph nodes in the high-RF-radiation group compared to the sham-RF-radiation group. However, additional histopathological analysis of the cage-control animals suggested that this difference was due to unusually low frequency of this type of tumor in the sham-RF-radiation group rather than a high frequency in the high-RF-radiation group. With respect to non-neoplastic findings, statistically significant differences between the RF-radiation groups and the sham-RF-radiation group were observed only for single findings in the lacrimal glands, lungs, liver and skin. Such changes are commonly seen in aged rats and were considered to be unrelated to RF radiation. The results of the present study do not support co-carcinogenic effects of low-level long-term RF-radiation exposure in rats.
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PMID:No effects of radiofrequency radiation on 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone-induced tumorigenesis in female Wistar rats. 1688 41

It is not surprising that cancer, a kind of derangement of development, hijacks DNA methylation, which is necessary for normal mammalian embryogenesis. Both decreases and increases in DNA methylation are a frequent characteristic of a wide variety of cancers. There is often more hypomethylation than hypermethylation of DNA during carcinogenesis, leading to a net decrease in the genomic 5-methylcytosine content. Although the exact methylation changes between different cancers of the same type are not the same, there are cancer type-specific differences in the frequency of hypermethylation or hypomethylation of certain genomic sequences. These opposite types of DNA methylation changes appear to be mostly independent of one another, although they may arise because of a similar abnormality leading to long-lasting epigenetic instability in cancers. Both tandem and interspersed DNA repeats often exhibit cancer-associated hypomethylation. However, one of these repeated sequences (NBL2) displayed predominant increases in methylation in some ovarian carcinomas and Wilms tumors and decreases in others. Furthermore, decreases and increases in CpG methylation can be interspersed within a small subregion of the 1.4-kb repeat unit of these tandem arrays. While the transcription-silencing role of DNA hypermethylation at promoters of many tumor-suppressor genes is clear, the biological effects of cancer-linked hypomethylation of genomic DNA are less well understood. Evidence suggests that DNA hypomethylation functions in direct or indirect control of transcription and in destabilizing chromosomal integrity. Recent studies of cancer-linked DNA hypomethylation indicate that changes to DNA methylation during tumorigenesis and tumor progression have a previously underestimated plasticity and dynamic nature.
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PMID:Cancer-linked DNA hypomethylation and its relationship to hypermethylation. 1690 14


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