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

The series of genetic changes leading to malignancy in colorectal cancer is well reported. This includes mutational activation of the proto-oncogene Ki-ras and mutation/deletion of the p53 tumour suppressor gene. The frequency of these mutations was investigated in a panel of 52 colorectal cancer patients using a combination of immunocytochemistry and non-radioactive, digoxigenin-labelled in situ hybridisation. Sixty two per cent (32 of 52) of the study population were positive for p53 overexpression and 36% (19 of 52) positive for Ki-ras mutation. Twenty seven per cent (14 of 52) of the patients expressed both mutations. Mutation of either the p53 or the Ki-ras gene did not correlate with Dukes's stage, tumour differentiation or 5 year survival rate of the patients. Most of the rectal carcinoma specimens (11 of 15) showed p53 over-expression but the significance of this was not supported statistically. Thus detection of molecular changes is becoming more amenable to incorporation into routine histological carcinoma assessment because of the advent of non-radioactive labelling in in situ hybridisation and antibodies suitable for paraffin wax embedded specimens. The significance of these mutations in disease prognosis, however, remains questionable.
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PMID:Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. 782 87

By successive screenings of cDNA libraries prepared from human tumours and from human foreskin keratinocytes, we have isolated overlapping cDNAs coding for a novel protein which we call Ron, with sequence characteristics of a receptor protein tyrosine kinase. Ron is a 1400 amino acid protein structurally similar to the 1408 amino acid product of the C-MET proto-oncogene, the receptor for hepatocyte growth factor and scatter factor. The two proteins have 63% overall sequence identity in their intracellular regions. We have localised the RON gene to human chromosome region 3p21, a region frequently deleted in small cell carcinoma of the lung and in renal cell carcinoma, and which is believed to harbour unidentified tumour suppressor genes. Interestingly, normal lung tissue contains transcripts of the RON gene.
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PMID:A novel putative receptor protein tyrosine kinase of the met family. 838 24

Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.
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PMID:Multiple genetic alterations in malignant metastatic insulinomas. 856 94

bcl-2 is a proto-oncogene which inhibits apoptosis. In contrast, p53 tumour suppressor gene is known to induce apoptosis. In this study we analysed immunohistochemically 63 mesenchymal tumours for the expression of bcl-2 and p53 proteins with a special emphasis on muscle-derived tumours. bcl-2 was expressed in all seven rhabdomyosarcomas and in five out of seven leiomyosarcomas. In benign muscle tumours, bcl-2 expression was found in all four epithelioid leiomyomas and in six out of 14 leiomyomas. In non-neoplastic muscle cells, occasional weak bcl-2 positivity was found in muscle cells of vascular walls and myometrium. In mesenchymal tumours of other lineages, bcl-2 positivity was only found in four out of 12 malignant fibrous histiocytomas and in one out of three liposarcomas. p53 positivity was found in 14 tumours, 13 of which were sarcomas. No association was found between p53 and bcl-2 positivity. Our results suggest that bcl-2 expression is activated significantly more often in muscle derived tumours than in mesenchymal tumours of other lineages. Our results also suggest that p53 status does not directly affect the expression of bcl-2 in sarcomas.
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PMID:bcl-2 is preferentially expressed in tumours of muscle origin but is not related to p53 expression. 883 22

The identification of tumour-specific chromosome abnormalities in a wide range of malignancies together with an understanding of their role in the activation of proto-oncogenes and loss of tumour suppressor genes has resulted in chromosome analysis of malignant cells beginning to provide information on the etiology of different malignancies. Two principle types of translocation have been identified. In the first, a protooncogene becomes juxtaposed to the enhancing or controlling elements of an immunoglobulin or T-cell receptor gene, resulting in deregulation of proto-oncogene expression. The second type results when breaks occur within a gene on each chromosome, creating a fusion gene that encodes for a chimaeric protein, usually a transcription factor. Homozygosity for loss of tumour suppressor gene function is frequently achieved by the inherited or somatic mutation of one allele together with a chromosome deletion of the region containing the other allele. The increasing knowledge of the mechanisms involved in the formation of cancer-specific chromosome abnormalities should help elucidate the causative role of environmental mutagens such as radiation.
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PMID:Chromosome changes in human cancer--are they pointers to mechanisms of initiation? 930 63

Prostatic adenocarcinoma is emerging as a major cause of morbidity and mortality in the male population in the western world. Programmed cell death (apoptosis) in the prostate is activated by hormone ablation and is under the control of several regulating genes including the tumour suppressor gene p53 and the proto-oncogene bcl-2. Bcl-2 belongs to a rapidly expanding family of genes which form two functionally antagonistic groups controlling cell death and survival. Apoptosis regulating genes appear to play an important role in the development and progression of prostatic adenocarcinoma and offer a potential target for future therapeutic strategies.
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PMID:Apoptosis regulating genes in prostate cancer (review). 953 52

Tumour suppressor genes may have a role in the control of trophoblast cell population expansion as trophoblast invasion occurs. To investigate this hypothesis, the location of tumour suppressor gene and proto-oncogene products were studied at various stages of trophoblast differentiation and invasion. Trophoblast and decidua were obtained from eight women having a therapeutic termination of pregnancy. Immunohistochemistry was used to localize the products of c-myc, c-erB-2, RB, BCL-2, P21, and P53 genes and anti-cytokeratin was used to identify fetal cells amongst the maternal decidual cells. The most differentiated and furthest invading trophoblast cell type, the multinucleated trophoblast, expressed a combination of genes which may indicate a high apoptotic rate. The other fully differentiated trophoblast, the syncytiotrophoblast, expressed BCL-2 suggesting protection from apoptosis. The co-occurrence of proto-oncogenes and the products of tumour suppressor genes in first trimester trophoblast suggests an important role not only in negative regulation of cellular invasion but also in population expansion through the presence of oncogenes and anti-apoptotic proteins.
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PMID:Oncogene and tumour suppressor gene products during trophoblast differentiation in the first trimester. 966 34

Radiosensitivity is a major hallmark of the human genetic disorder ataxia telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vivo after exposure of patients to therapeutic doses of radiation and in cells in culture. Clearly an understanding of the nature of the molecular defect in ataxia telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas, the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia telangiectasia (A-T)? As outlined above, since radiosensitivity is a universal characteristic of A-T, understanding the mechanism of action of ATM will provide additional information on radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM-controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense cDNA constructs into tumours to achieve the same end-point.
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PMID:Radiosensitivity and oxidative signalling in ataxia telangiectasia: an update. 968 57

Injected DNA proceeds with certain probabilities through the following steps: degradation by serum nucleases, adsorption to cells, uptake into cells, ligation to other DNA, mutation, expression of unintegrated DNA, integration, expression of integrated DNA, and activation of or inactivation of cellular genes. The maximal probability per DNA molecule of each of these steps is estimated based on experimental results in cell culture with transfection of DNA and with infection by retroviruses. A maximum cumulative probability of having a harmful effects is calculated to be less than 10(-16) to 10(-19) per DNA molecule from a cell without activated proto-oncogenes or active viral oncogenes. The most frequent harmful effects considered are inactivation of a tumour suppressor gene and activation of a proto-oncogene. Such inactivation and activation in a cell that could give rise to cancer would increase the age-standardized incidence of cancer by a small amount. The amount of increase would differ among individuals depending upon their genotypes and their environments. Thus, the magnitude of the increase will depend upon the frequency of more sensitive individuals. The probability of an increased incidence of cancer as a possible effect of the vaccination should be compared to the number of DNA molecules to be injected per person and to the protective effects of successful HBV vaccine.
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PMID:Overview of biological effects of addition of DNA molecules to cells. 973 75

Many studies have tried to discriminate malignant from benign phaeochromocytomas, but until now no widely accepted histological, immunohistochemical, or molecular methods have been available. In this study of 29 malignant and 85 benign phaeochromocytomas from 102 patients, immunohistochemistry was performed with antibodies to the tumour suppressor gene product p53 and the proto-oncogene products bcl-2 and c-erbB-2, using the avidin-biotin complex method. Malignant phaeochromocytomas showed a statistically significant higher frequency of p53 (p=0.042) and bcl-2 (p=0.037) protein expression than their benign counterparts. The combination of both markers showed an even higher significance (p=0.004), to which both markers contributed equally. Overexpression of c-erbB-2 was associated with the occurrence of familial phaeochromocytomas (p=0. 001), but no difference was found between benign and malignant cases. In conclusion, p53, bcl-2, and c-erbB-2 all appear to be involved in the pathogenesis of a proportion of phaeochromocytomas. Immunoreactivity to p53 and bcl-2 proteins may help to predict the clinical behaviour of phaeochromocytomas.
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PMID:Prognostic value of p53, bcl-2, and c-erbB-2 protein expression in phaeochromocytomas. 1062 68


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