Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In situ hybridization was used to characterize the expression pattern of the T:G mismatch-specific thymidine-DNA glycosylase (TDG) gene, encoding a DNA repair enzyme which corrects G:T mismatches that result from the hydrolytic deamination of 5-methyl cytosines. TDG transcripts were uniformly and ubiquitously expressed from 7.5-13.5 days post-coitum, but were then markedly enriched in specific tissues of the developing fetus. At 14.5 gestational days, TDG was strongly expressed in the developing nervous system, thymus, lung, liver, kidney and intestine. At later stages, high levels of expression were detected in the thymus, brain, nasal epithelium and within proliferating regions of the intestine, skin, kidney, teeth and bone. This pattern of expression strongly correlated with those of the methyl transferase (MTase) gene, coding for the enzyme which specifically methylates CpG dinucleotides, and the p53 tumour suppressor gene. However, TDG and MTase were differentially expressed during maturation of the male and female germline. We also report that tumors occuring in mice which overexpress MMTV-v-Ha-ras or MMTV-c-myc transgenes or mice heterozygous for p53 gene disruption, all show elevated TDG and MTase expression specific to the transformed tissue.
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PMID:Expression of T:G mismatch-specific thymidine-DNA glycosylase and DNA methyl transferase genes during development and tumorigenesis. 979 35

Two molecular pathways leading to cancer are known. Common-type cancers arise from the 'tumour suppressor' pathway, characterized by gross chromosomal changes and allelic losses (LOH) in an average of 25 per cent or more of randomly chosen chromosomal loci. The 'mutator pathway' has been recognized in a subset of cancers, characterized by widespread microsatellite DNA instability and rarity of chromosomal losses. The present study has investigated 20 pancreatic endocrine tumours (PETs) for loss of heterozygosity (LOH) at seven chromosomal loci (3p14, 7q31-32, 11q13, 13q14, 18q21, 17p13, and 17q21); microsatellite instability; and Ki-ras, N-ras, and p53 gene mutations. LOH was found in an average of 24 per cent of the chromosomal loci analysed. No tumour showed microsatellite instability. Ki-ras and p53 mutations were each found in one case. The frequency of losses was higher in malignant (40 per cent) than in benign (17 per cent) tumours (p = 0.009), and the specific chromosome 17p13 LOH was associated with extrapancreatic extension of disease (p = 0.007), high proliferative activity (p = 0.001), and absence of progesterone receptors (p = 0.01). A common deleted region on chromosome 17p13 and the rarity of p53 gene mutations suggest the existence of a novel tumour suppressor gene involved in the pathogenesis of PETs in this chromosomal area.
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PMID:Pancreatic endocrine tumours: evidence for a tumour suppressor pathogenesis and for a tumour suppressor gene on chromosome 17p. 987 39

The mammalian SWI/SNF complex is a chromatin remodelling complex that uses the energy of ATP hydrolysis to facilitate access of transcription factors to regulatory DNA sequences. This complex, that was initially described as a co-factor for nuclear receptors, has recently been associated with the control of cell growth. Two of the subunits known as BRG-1 and brm can associate with the Retinoblastoma tumour suppressor gene product and co-operate with this protein for repression of E2F activity. In addition, expression of brm is frequently down-regulated upon cellular transformation and re-introduction of this protein into fibroblasts transformed by activated ras induces partial reversion of the transformed phenotype. Finally, the hSNF5/INI1 gene, encoding another subunit of the SWI/SNF complex, is subject to bi-allelic mutations in rhabdoid tumours, a very aggressive form of paediatric cancers. These observations provide a novel link between malignant transformation and chromatin remodelling machineries.
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PMID:The mammalian SWI/SNF complex and the control of cell growth. 1044 Oct 69

Malignant melanoma is the deadliest form of skin cancer. Previous studies have shown that the incidence of ras mutation increases with progression of melanoma, but that such mutations may not be present in the earliest radial growth phase melanomas. Recently it has been proposed that introduction of ras mutations into cells deficient in tumour suppressor genes such as p16 (INK4a) is sufficient to induce characteristics of cellular transformation such as anchorage-independent growth and tumour formation in vivo. To test this hypothesis in human melanoma, mutant N-ras, mutant H-ras or wild-type H-ras genes were transfected by electroporation into WM35 cells, a p16-deficient human melanoma cell line of low invasive potential. Increased expression of mutant ras p21 enhanced anchorage-dependent cell growth on tissue culture plastic. In addition, overexpression of mutant N-ras and H-ras, but not of wild-type H-ras, increased the experimental invasive potential, inducing anchorage-independent growth in soft agar, increasing cell motility measured by time-lapse video microscopy, and increasing invasiveness through reconstituted basement membranes. Finally, overexpression of mutant H-ras in melanoma cells was shown to increase tumorigenicity and to induce cachexia when H-ras transfected cell lines were injected subcutaneously in severe combined immunodeficiency (SCID) mice. Thus the addition of activating ras mutations to a melanoma cell line already deficient in p16 leads to enhanced proliferation, survival and migration in vitro and to enhanced subcutaneous tumour formation in vivo. This phenotype is typical of the behaviour of vertical growth phase (VGP) melanoma, and we propose that activation of the ras signalling pathway in the presence of deletions in p16 or related tumour suppressors can induce the VGP melanoma phenotype.
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PMID:Overexpression of mutant ras in human melanoma increases invasiveness, proliferation and anchorage-independent growth in vitro and induces tumour formation and cachexia in vivo. 1046 84

Alterations of onco/tumour suppressor genes are involved in the formation of human hematological malignancies. Previously, in animal models, we demonstrated the applicability of in vivo gene expression investigations to monitor the effects of certain carcinogenic chemicals. In our present study we determined the expression of onco/suppressor genes from isolated peripheral white blood cells of patients with chronic myeloid leukaemia (CLL) and non-Hodgkin lymphoma (NHL). Gene expressions were determined by isolation of total RNA and slot blot hybridization with chemiluminescently labeled gene probes (Ha-ras, c-myc and p53) Expression levels were compared before and after treatment with a combined cytostatic protocol, containing cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). Both the CLL and NHL group of patients exhibited significantly higher expression of the investigated genes than healthy controls. One month after the cytostatic treatment, we found considerably fewer individuals with overexpressed oncogenes than before the treatment. Our study proved that onco/tumour suppressor gene expressions could be used as biomarkers of certain hematological malignancies, and to monitor the therapeutical effect of cytostatic drugs.
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PMID:The usefulness of in vivo gene expression investigations from peripheral white blood cells: a preliminary study. 1049 9

Small amounts of free DNA circulate in both healthy and diseased human plasma/serum, and increased concentrations of DNA are present in the plasma of cancer patients. Characteristics of tumour DNA have been found in genetic material extracted from the plasma of cancer patients. These features include decreased strand stability and the presence of specific oncogene, tumour suppressor gene and microsatellite alterations. Point mutations of the ras genes have been detected in the plasma DNA of patients suffering from haematopoetic malignancies, colorectal and pancreatic cancer, sometimes prior to clinical diagnosis. Rearranged immunoglobulin heavy chain DNA has been found in the plasma of patients with non-Hodgkins lymphoma and acute B cell leukaemia. Microsatellite instability, expressed either as a new allele or a loss of one allele (LOH) occurs in the plasma and serum DNA of patients suffering from head and neck, lung and renal cell cancer. The results obtained in many different cancers have opened a new research area indicating that plasma DNA might eventually be a suitable target for the development of non-invasive diagnostic, prognostic and follow-up tests for cancer.
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PMID:Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients. 1050 46

Cancer development requires the accumulation of numerous genetic changes which are usually believed to occur through the presence of unrepaired DNA lesions. Exogenous or endogenous DNA-damaging agents can lead to mutations in the absence of efficient error-free repair, via replication of DNA damage. Several DNA repair pathways are present in living cells and well-conserved from bacteria to human cells. The nucleotide excision repair (NER), the most versatile of these DNA repair systems, recognizes and eliminates a wide variety of DNA lesions and particularly those induced by ultraviolet (UV) light. The phenotypic consequences of a NER defect in humans are apparent in rare but dramatic diseases characterized by hypersensitivity to UV and a striking clinical and genetic heterogeneity. The xeroderma pigmentosum (XP) syndrome is a human disorder inherited as an autosomal recessive trait. Persistence of unrepaired DNA damage produced by exposure to UV light is associated, in the XP syndrome, with an extremely high level of skin tumors in sun-exposed sites. Several key genes are mutagenized by UV-light and are responsible for skin cancer development. Mutations are found on ras oncogenes, p53 and PTCH tumour suppressor genes in skin cancers from DNA repair proficient as well as XP patients. The typical signature of UV-induced mutations found on these genes allows one to conclude that the uvB part of sunlight is responsible for the initiation of the carcinogenesis process.
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PMID:The molecular pathways of ultraviolet-induced carcinogenesis. 1051 72

The interpretation of cancer as a somatic evolutionary process involving genetic mutation followed by selection, traces its origins to the early years this century. The dramatic developments in molecular genetics have substantiated these early ideas. Through the application of positional cloning and genomic analysis, many mutations in particular genes, both dominant oncogenes and tumour suppressor genes have now been found in a wide variety of tumours. Other genetic events such as non-disjunction leading to haploid expression of a gene and so reduced gene dosage, or epigenetic changes following, for example, changes in methylation patterns leading to reduced or increased gene expression, may also play critical roles in the progression of a cancer. The analysis of mutations at different stages of colorectal cancer provides a good model for following the initiation and progression of a cancer. Mutations in the APC gene, which explain familial adenomatous polyposis, occur in a high proportion of sporadic colorectal carcinomas and appear to be the earliest known changes. Patterns of mutation in the gene suggest dominant negative or gain of function effects, and also reveal important low penetrance subpolymorphic missense mutations that nevertheless may have a very significant impact on the genetic contribution to colorectal cancer susceptibility. Mutations are also found in related genes in the APC pathway, such as beta-catenin and E-cadherin. Mutations in mismatch repair genes (hMLH1 and hMSH2) have also been shown to occur, as well as reduced expression due to methylation changes, in 10% to 20% of sporadic colorectal carcinomas. In addition, mutations in the well known oncogenes p53 and ras are commonly found. The growth of a cancer is a balance between the rate of cell division and the rate of cell death or apoptosis. Thus, genetic changes which reduce the probability of apoptosis, such as p53 and probably hMLH1, are as important a feature of the evolution of a cancer as those which enhance the independence (APC) and rate of cell division (growth factors). Simple models for the evolution of a cancer that take into account these two processes, show that cancers evolve initially by a series of finite increases in cell population size, following which there may be long periods of cell turnover during which there is an opportunity for further mutation and selection. This explains the long lag periods between the initiation and subsequent progression of most cancers. Our rapidly developing understanding of cancers at the fundamental genetic level provides new opportunities for developing targeted treatments, as well as novel approaches to prevention and early detection.
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PMID:1998 Runme Shaw Memorial Lecture: somatic evolution of cancer. 1057 14

The tumour suppressor PTEN, also named MMAC1 or TEP1, is associated with a number of malignancies in human populations. This protein has a dual protein phosphatase activity, being also capable to dephosphorylate phosphatidylinositol 3,4,5 triphosphate. We have studied the mechanism of growth suppression attributable to PTEN. We observed that PTEN overexpression inhibits cell growth in a variety of normal and transformed, human and murine cells. Bromodeoxyuridine (BrdU) incorporation and TUNEL labelling experiments in transiently transfected cells demonstrate that this inhibition is due to a cell cycle arrest rather than induction of apoptosis. Given that PTEN is unable to cause cell growth arrest in retinoblastoma (Rb)-deficient cell lines, we have explored the possible requirement for pRb in the PTEN-induced inhibition of cell proliferation. We found that the co-expression of SV40 antigen, but not a mutant form (which binds exclusively to p53), and cyclin D1/cdk4 are able to overcome the PTEN-mediated growth suppression. In addition, the reintroduction of a functional pRb, but not its relatives p107 or p130, in Rb-deficient cells restores the sensitivity to PTEN-induced arrest. Finally, the hyperphosphorylation of transfected pRb is inhibited by PTEN co-expression and restored by PI-3K co-expression. Accordingly, PTEN gene is mostly expressed, in parallel to Akt, in mid-late G1 phase during cell cycle progression prior to pRb hyperphosphorylation. Finally, we have studied the signal transduction pathways modulated by PTEN expression. We found that PTEN-induced growth arrest can be rescued by the co-expression of active PI-3K and downstream effectors such as Akt or PDK1, and also certain small GTPases such as Rac1 and Cdc42, but not by active Ha-ras, raf or RhoA. Collectively, our data link the tumour suppressor activities of PTEN to the machinery controlling cell cycle through the modulation of signalling molecules whose final target is the functional inactivation of the retinoblastoma gene product.
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PMID:PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein. 1060 5

The aim of this study was to study the protein expression of six proto-oncogenes (epidermal growth factor receptor (EGFR), c-fms, c-myc, c-kit, c-erbB-2 and pan-ras) and one tumour suppressor gene (TP53), by immunohistochemical staining of normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia (CIN). Paraffin sections of 45 normal cervical specimens, 38 CIN grade one (CIN1), 37 CIN2 and 43 CIN3 were studied. An immunohistochemical (IHC) score was derived from the intensity of staining and the percentages of cells stained. In normal cervical specimens, a higher IHC score was found with EGFR and c-fms in superficial (S), intermediate (I) and parabasal (PB) cells compared with basal cells. In contrast, a higher IHC score was found with c-erbB-2 in basal cells in normal cervical specimens. Dysplastic cells in CIN had a higher IHC score with c-myc and c-erbB-2 than normal S/I and PB cells. Dysplastic cells had a higher score with EGFR than normal basal cells. However, a higher IHC score with EGFR and c-fms was found in normal S/I cells than dysplastic cells. These findings suggested that EGFR and c-fms were activated in more differentiated normal cells but were less active in less differentiated normal basal cells. However, EGFR was reactivated in dysplastic cells. Meanwhile, c-erbB-2 was activated in less differentiated normal basal cells and dysplastic cells, and was less active in differentiated normal cells. c-myc was activated in dysplastic cells. c-fms was more active in more differentiated normal cells and was not activated in less differentiated or dysplastic cells. c-kit, pan-ras and TP53 were not activated in normal nor dysplastic cervical cells. These results suggest EGFR, c-erbB-2 and c-myc may be important proto-oncogenes in CIN and that antibodies or anti-genes targeted against them may alter the progress of CIN to invasive cancer.
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PMID:Proto-oncogenes and p53 protein expression in normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia. 1067 85


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