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)

Transcription of the retinoic receptor beta (RARbeta) gene is activated in a ligand-dependent manner by the retinoic acid receptor alpha. Reduced RARbeta gene expression and loss of ligand inducibility are frequently observed in human carcinoma cells indicating that such alterations might contribute to carcinogenesis. In this study we have analyzed the influence of RARbeta on cervical cancer cell growth. Transfection of HeLa cells with RARbeta expression plasmids resulted in reduced clonal cell growth in the presence of retinoic acid (RA). RA-induced growth inhibition in HeLa x fibroblast hybrid cells was partially relieved by a dominant-negative RARbeta mutant. HeLa clones stably expressing a RARbeta transgene under control of the human beta-actin promoter [HeLa(RARbeta)] were established and analyzed for transgene-mediated growth alterations in vitro and in vivo. Anchorage-independent growth of the HeLa(RARbeta) lines was indistinguishable from that of control cells in the absence of RA, but strongly impaired after RA treatment. Reduced tumor growth of HeLa(RARbeta) clones was associated with high RARbeta protein levels. Somatic cell fusion experiments revealed that the loss of ligand inducibility of RARbeta gene expression in HeLa cells cannot be complemented by fusion with other cervical cancer cell lines. Our data indicate, firstly, that RARbeta is a negative regulator of tumor cell growth and, secondly, that cancer-associated defects in RARbeta gene expression are caused by stable, non-complementable silencing mechanisms.
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PMID:Growth inhibition of cervical cancer cells by the human retinoic acid receptor beta gene. 1062 91

Discovery of tumor suppressor genes has provided a rational approach to cancer prevention and treatment. Loss of retinoblastoma susceptibility gene (Rb) function is a rate-limiting event in the development of human and mouse cancers. Establishment of animal models of cancer associated with Rb deficiency allowed us to develop and test long-awaited approaches to genetic correction for treating tumors in vivo. Recent studies demonstrated that (1) prevention of carcinogenesis is achieved by correction of gene copy number in Rb+/- mice, and (2) reconstitution of Rb gene functions is sufficient for suppression of neoplasia in immunocompetent mice. These results fulfill a promise of cancer treatment by reconstitution of tumor suppressor function.
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PMID:A paradigm for cancer treatment using the retinoblastoma gene in a mouse model. 1066 99

High alcohol and low folate intake are independent risk factors for colorectal cancer. Acetaldehyde has been postulated to be a factor responsible for ethanol-associated carcinogenesis. High levels of acetaldehyde accumulate in the large intestine via the microbial oxidation of alcohol. Acetaldehyde degrades folate in vitro. Thus, it is possible that high intracolonic acetaldehyde levels break down folate in the colon. Our aim was to test the effect of high alcohol and acetaldehyde concentrations in the gut on systemic and local intestinal folate levels in rats. Twenty rats received 3 g/kg of ethanol twice a day for 2 weeks with or without concomitant ciprofloxacin administration. Twenty control rats received saline with or without ciprofloxacin. All rats were fed a diet with normal folate content. Alcohol treatment led to very high intracolonic acetaldehyde levels (387 +/- 185 microM), which were markedly decreased by concomitant ciprofloxacin treatment (21 +/- 4 microM). Erythrocyte, serum and small intestinal folate levels were unaffected by alcohol treatment. Alcohol administration decreased significantly colonic mucosal folate levels by 48%, and this effect was prevented by ciprofloxacin. We conclude that alcohol administration for 2 weeks leads to local folate deficiency of colonic mucosa in rats, most probably via the degradation of folate by the high levels of acetaldehyde microbially produced from ethanol. Our findings offer a unique explanation for the increased risk of colonic cancer associated with alcohol intake and folate deficiency.
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PMID:Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency. 1073 42

Mucins and simple mucin-type carbohydrates are cancer-associated antigens in several human tumors. Expression of Tn, sialosyl-Tn, Thomsen-Friedenreich (T), sialosyl-T and of a recently identified mucin-like glycoprotein (gp230) has not yet been thoroughly investigated in human cervix carcinogenesis. In the present study sections from normal cervix (n=10), CIN III lesions (n=10), and invasive carcinomas (n=47) were evaluated immunohistochemically using monoclonal antibodies. In normal cervix there was: cytoplasmatic expression of Tn in 1 case (10%); membranous expression of STn in 8 cases (80%); no expression of T and cytoplasmatic expression of ST in 1 case (10%); gp 230 was expressed in all cases with a membranous pattern. In CIN III lesions there was cytoplasmatic and membranous expression of Tn in 3 cases (30%) and of STn in 9 cases (90%); T and ST were not expressed; gp 230 was expressed in 5 cases (50%) both in the cytoplasm and at the cell membrane. In invasive carcinomas we observed Tn expression in 30 cases (63.8%) and STn in 31 cases (66%); T antigen was not expressed; expression of both ST and gp 230 in 24 cases (51.1%); all antigens showed membranous and cytoplasmatic staining. Our results show that Tn and ST are good markers of invasive carcinomas of the human cervix. We have also shown that loss of expression of the mucin-like glycoprotein gp 230 is associated with malignant transformation at a preinvasive stage.
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PMID:Simple mucin-type carbohydrate antigens (Tn, sialosyl-Tn, T and sialosyl-T) and gp 230 mucin-like glycoprotein are candidate markers for neoplastic transformation of the human cervix. 1099 78

The role of specific morphogens is well established in the determination of body plans in development. A variety of morphogens have been identified; others are suspected. Pathways have been delineated. In complex tissues, the ability to maintain fidelity of microarchitectural structure is crucial. Microarchitecture is a consequence of relationships among cells, not a function of single cells. Epithelial layers, in particular, are able to maintain their microarchitecture with remarkable accuracy over many decades despite recurrent damage, regular cell turnover, and complexity of structure. Nonetheless, metaplasia and transdifferentiation (change in tissue structure without cell dysplasia) do occur, suggesting that there is the possibility of loss of control or change of control of the microarchitecture. A strong inference to be derived from the above is that there are control systems and molecules and that these are derived from cells that are outside, but plausibly adjacent to, the respective epithelia. It is postulated is that there are morphogen-like controller molecules with morphogen-like functions in adult epithelial tissues. These are responsible for the maintenance of normal tissue microarchitecture. Because the function of these putative molecules is maintenance of tissue structure, I have chosen to call them morphostats by analogy with morphogens. It seems plausible that morphostats and morphogens may constitute overlapping families of molecules. Evidence for the existence of morphostats can be derived from a variety of in vivo and in vitro data and from studies of normal tissue, precancer, and cancer, including: (a) the existence but rarity of metaplasia and transdifferentiation; (b) the fact that metaplasias are multicentric and are only one step from normal but do not show any consistent epithelial mutation; (c) the genesis of animal cancers by simple transplantation of tissues into the wrong environment and the evidence that epithelial mutation is not a feature of such transplantation carcinogenesis; (d) the fact that carcinogenesis occurs frequently at the junctions of different epithelial types, e.g., squamocolumnar junctions in gastrointestinal and genital tracts; (e) the fact that cancer-associated fibroblasts can stimulate proliferation in transformed cells but not influence normal cells; and (f) the failure to grow most epithelial organs in a fully differentiated structural pattern in monolayer culture. It is suggested that morphostats may function like morphogens inasmuch as they may act via a diffusion gradient from source mesenchymal cells and provide architectural instruction for complex adult epithelia. Morphostats may influence architecture via control of cell adhesion, apoptosis, and proliferation. Some specific predictions follow from this hypothesis, most notably, a new two-hit model of cancer: one mutation in an epithelial cell resulting in disruption of cell function and structure (e.g., dysplasia); and the other in a mesenchymal or other supporting cell resulting in disruption of tissue microarchitecture. The corollary of this is that there will be mesenchymal mutations producing microarchitectural abnormalities without epithelial dysplasia and vice versa. Disruption of the functions of morphostats may result in a variety of abnormalities. Such disruption may be a key event in carcinogenesis.
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PMID:Morphostats: a missing concept in cancer biology. 1130 83

FRAT1 and FRAT2 are cancer-associated genes encoding GSK-3beta-binding proteins. Over-expression of FRAT1 or FRAT2 lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway. We have previously cloned and characterized FRAT2. Here, we found that FRAT1 and FRAT2 genes were clustered in the human chromosome 10q24.1 region. Blast search revealed that FRAT1 and FRAT2 genes, consisting of a single exon, were located together on human genome draft sequences AC006098.1 and AL355490.7, corresponding to the human chromosome 10q24.1 region. FRAT1 and FRAT2 genes were clustered in a tail to tail manner with an interval of about 10.7 kb. The 2.7-kb FRAT1 mRNA was relatively highly expressed in fetal brain, adult spleen, pancreas, HeLa S3 (cervical cancer), and K-562 (chronic myelogenous leukemia). FRAT1 and FRAT2 were co-expressed in 7 gastric cancer cell lines and 10 cases of primary gastric cancer, and were up-regulated together in gastric cancer cell line TMK1 and 2 cases of primary gastric cancer. These results indicated that FRAT1 and FRAT2 genes were up-regulated together in several cases of human gastric cancer. Up-regulation of FRAT1 and FRAT2 in gastric cancer might lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway.
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PMID:FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer. 1144 44

Two thiophosphoroate compounds WR-2721 and WR-151327 were assessed for their ability to modify the deleterious effects (life shortening and carcinogenesis) of fission-spectrum neutrons (kerma-weighted mean energy of 0.85 MeV) or gamma rays on B6CF1 hybrid mice. Male and female mice, 200 of each sex per experimental group, were irradiated individually at 110 days of age. Radioprotectors (400 mg/kg of WR-2721 or 580 mg/kg of WR-151327) were administered intraperitoneally 30 min prior to irradiation. Neutron doses were 10 cGy or 40 cGy and gamma ray doses were 206 cGy or 417 cGy. Animals were housed five to a cage; cage locations in the holding rooms were randomized by computer. Animals were checked daily and all deceased animals were necropsied. WR-2721 afforded protection against both neutron- and gamma-ray-induced carcinogenesis and subsequent life shortening. Cumulative survival curves for unirradiated mice of either sex were unaffectecd by protectors. WR-2721 protected irradiated groups against life shortening by approximately 10 cGy of neutrons or 100 cGy of gamma rays. WR-151327 was as effective as WR-2721 against neutron irradiation.
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PMID:Protection by WR-2721 and WR-151327 against late effects of gamma rays and neutrons. 1153 16

Circulating tumor DNA in plasma and serum has been demonstrated to reflect the biological characteristics of tumors, including the rates of apoptosis and necrosis. Aberrant promoter methylation has increasingly emerged as a fundamental molecular abnormality associated with loss of critical gene functions during carcinogenesis. This epigenetic inheritance has significant biological implications for early tumor initiation and cancer progression or metastasis formation. The promoter-region methylation is crucial in transcriptional silencing of tumor suppressor genes, DNA repair genes, and metastasis inhibitor genes, and is linked to the predisposition of genetic alterations of other cancer-associated genes. Of clinical relevance, epigenetic markers in plasma and serum have recently been established as specific and sensitive biomarkers for early and noninvasive screening, risk assessment, and monitoring of neoplastic diseases. A panel of epigenetic markers may possibly allow the detection of circulating tumor DNA in virtually all patients with different cancer types. Furthermore, the prognostic value of aberrant DNA methylation and therapeutic implications of demethylation of methylated genes could further improve the management of patients with different kinds of cancer.
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PMID:Epigenetic tumor markers in plasma and serum: biology and applications to molecular diagnosis and disease monitoring. 1170 93

Squamous epithelial dysplasia is frequently encountered in the cancerous esophagus. However, its biological and clinical significance have not yet been fully elucidated. Investigations in squamous cell dysplasia of the esophagus have been performed to date in our department. We consider dysplasia to be the earliest malignancy of the esophagus based on such biologic features as the histopathologic findings, the proliferative activity, and the altered expression of cancer-associated genes. It is essential to detect and treat these early lesions endoscopically. Hopefully the findings of further studies of dysplasia can help to elucidate the mechanism of carcinogenesis in esophageal squamous cell carcinoma.
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PMID:Biologic and clinical significance of squamous epithelial dysplasia of the esophagus. 1182 83

One form of defence against cancer development involves a series of genes whose role is to metabolize and excrete potentially toxic compounds and to repair subtle mistakes in DNA. Much laboratory and epidemiological research over the past decade has concentrated on the identification of these genes and an assessment of their role in cancer aetiology. Of particular interest has been whether the risk of cancer associated with a particular environmental exposure differs with respect to functionally different polymorphisms of these genes, i.e. gene-environment interaction. A large number of studies have been conducted for numerous genes and also for all common cancer sites, although results have been very inconsistent and therefore inconclusive. This is partially due to the inadequate sample size of most studies to detect modest effects and the over-reporting of positive associations identified in subgroups of the dataset. There is also much confusion about the meaning of "gene-environment interaction", what type of studies should be conducted to study it and also how it should be measured. Furthermore, the very purpose of these studies is not clear; are they attempting to identify high-risk individuals, or are they simply trying to further understand the cancer process? This review will explore these questions and provide some recommendations to help ensure that the next phase of gene-environment interaction studies, which are likely to be much larger and based on many more genes, also provide some clearer answers.
Carcinogenesis 2002 Mar
PMID:Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it? 1250 39


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