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)

Cancer is now considered to be a multi-hit process which involves a number of aberrant genetic events culminating in malignant transformation. In squamous cell carcinoma (SCC) of the head and neck the action of both oncogenes and tumour-suppressor genes has been identified during the course of the disease. Cytogenetic analysis of these carcinomas has demonstrated chromosomal breakpoints, particularly in the regions of 1p22 and 11q13 together with frequent amplification of the proto-oncogenes in the 11q13 amplicon; int-2, hst-1 and bcl-1. Ras mutations have been infrequently identified in the Western World whereas ras over-expression has been a common finding and may be associated with the early development of head and neck cancer. C-myc over-expression appears to correlate with a poor prognosis for these patients. The tumour-suppressor gene p53 is also thought to be involved in the development of SCC in head and neck tumours and its aberrant expression is associated with a history of heavy smoking and heavy drinking. E-cadherin, a putative tumour-suppressor gene is down-regulated in poorly differentiated head and neck SCC and maybe important in nodal metastasis. A recent study has indicated that the Human Papilloma Virus (HPV 16 and 33) has a role in the aetiology of tonsillar carcinomas and HPV has been shown to produce transforming proteins which bind to and inactivate the p53 tumour suppressor gene. This evidence suggests that the possibility of a viral mechanism for the development of SCC in the head and neck should be considered. This paper proposes a series of genetic events to explain the development of SCC of the head and neck.
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PMID:Oncogenes and tumour-suppressor genes in squamous cell carcinoma of the head and neck. 133 Jan 49

Radon increases the risk of lung cancer in smoking and non-smoking underground miners. To investigate the mutational spectrum associated with exposure to high levels of radon, we sequenced exons 5-9 of the p53 tumour suppressor gene and codons 12-13 of the Ki-ras protooncogene in 19 lung cancers from uranium miners exposed to radon and tobacco smoke. Mutations were not found in Ki-ras, but 9 p53 mutations, including 2 deletions, were found in 7 patients by direct DNA sequencing after polymerase chain reaction amplification of DNA from formalin-fixed, paraffin-embedded tissue. In tumours from 5 patients, the mutation produced an aminoacid change and an increased nuclear content of p53 protein. The tumours with either a stop codon or frame-shift deletion in the p53 gene were negative by immunohistochemistry. None of the mutations were G:C to T:A transversions in the coding strand of the p53 gene, which are the most frequent base substitutions associated with tobacco smoking, and none were found at the hotspot codons described in lung cancer. The observed differences from the usual lung cancer mutational spectrum may reflect the genotoxic effects of radon.
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PMID:Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. 134 94

RFLP (restriction fragment length polymorphism) analysis in 46 ovarian tumour and paired blood samples shows that 33 per cent (5/15) of informative carcinomas had loss of heterozygosity (LOH) at 11p15.4 (Calcitonin locus) and 18% (4/22) had LOH at 11p15.5 (Ha-ras). No LOH was detected in five borderline and four benign ovarian tumours. Analysis of survival in the carcinoma group (37 patients) showed a significantly poorer survival in patients whose tumours showed LOH at either or both of these 11p loci (chi 2 = 7.771, p = 0.005). This suggests the presence of a tumour suppressor gene (tsg) on the short arm of chromosome 11 whose loss is associated with particularly aggressive disease.
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PMID:Allele loss on chromosome 11p is associated with poor survival in ovarian cancer. 136 Aug 88

The multistep development of haematopoietic malignancies, like other neoplasms, reflects sequential mutations that either activate proto-oncogenes or disrupt tumour suppressor genes. In a few spontaneous leukaemias or lymphomas, more than one mutation has now been identified, and the experimental analysis of oncogene co-operation is advancing rapidly via retroviral gene delivery and characterization of transgenic mice bearing oncogenes. In transgenic models, tumorigenesis can be accelerated by introducing another oncogene or by using a retrovirus as an insertional mutagen to identify cellular genes that collaborate with the transgene. Leukaemogenesis can be promoted by some ten pairs of oncogenes. The myc nuclear oncoprotein, for example, can collaborate with cytoplasmic oncoproteins such as ras, raf, bcl-2, pim-1 and v-abl, as well as with nuclear products such as bmi-1 or the tumour suppressor p53. The genes in such partnerships seem to provide complementary functions. For example, myc seems to prevent cells from becoming quiescent, whereas bcl-2 blocks programmed cell death; and others, for example ras, may diminish growth factor requirements. The products of genes that collaborate may lie on separate signal transduction pathways, leading to distinct nuclear targets. Key targets are postulated to be regulators of the cell cycle, especially the cyclins and associated kinases that govern progression in the G1 phase.
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PMID:Oncogene co-operation in leukaemogenesis. 145 Nov 8

Point mutations in the p53 gene are the most frequently identified genetic change in human cancer. They convert murine p53 from a tumour suppressor gene into a dominant transforming oncogene able to immortalize primary cells and bring about full transformation in combination with an activated ras gene. In both the human and murine systems the mutations lie in regions of p53 conserved from man to Xenopus. We have developed a monoclonal antibody to p53 designated PAb240 which does not immunoprecipitate wild type p53. A series of different p53 mutants all react more strongly with PAb240 than with PAb246. The PAb240 reactive form of p53 cannot bind to SV40 large T antigen but does bind to HSP70. In contrast, the PAb246 form binds to T antigen but not to HSP70. PAb240 recognizes all forms of p53 when they are denatured. It reacts with all mammalian p53 and chicken p53 in immunoblots. We propose that immunoprecipitation of p53 by PAb240 is diagnostic of mutation in both murine and human systems and suggest that the different point mutations which convert p53 from a recessive to a dominant oncogene exert a common conformational effect on the protein. This conformational change abolishes T antigen binding and promotes self-oligomerization. These results are consistent with a dominant negative model where mutant p53 protein binds to and neutralizes the activity of p53 in the wild type conformation.
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PMID:Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. 169 10

We have detected allelic loss in a majority of prostate cancers analysed. These losses have been detected on several chromosomes known to harbour tumour suppressor genes important in the development of other tumour types. Elevated rates of loss of heterozygosity on chromosome 16q and 10q suggest that tumour suppressor genes important in the pathogenesis of prostate cancer may be present on these chromosomes. Conversely, determination of the frequency of ras gene mutations in prostate cancer tissue suggests that these genetic alterations play a minor part in both the initiation and progression of this disease in humans.
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PMID:Genetic changes associated with prostate cancer in humans. 184 50

Studies of multistage carcinogenesis in mouse skin have provided many of the early concepts of tumour initiation, promotion and progression. Genetic approaches have led to the identification of a number of mutational alterations in proto-oncogenes and tumour suppressor genes which take place at specific stages of carcinogenesis in this particular system. Initiation involves, at least in a proportion of tumours, mutational activation of the cellular H-ras proto-oncogene. Trisomy of chromosome 7, which develops during the premalignant clonal expansion phase, possibly as a consequence of tumour promoter treatment, is followed by further alterations on chromosome 7 which lead to a relative increase in the expression of mutant ras alleles. The p53 tumour suppressor gene undergoes mutational alteration and loss of heterozygosity in a proportion of squamous carcinomas but this particular gene does not appear to be involved in the further transition of squamous carcinomas to highly undifferentiated spindle cell tumours. The latter transition appears to be a recessive event which can be complemented by fusion with cells at earlier stages of malignancy. Mouse skin carcinogenesis therefore continues to provide invaluable information on the nature of the genetic and biological transitions which occur during the step-wise progression of normal cells to malignancy.
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PMID:Functional loss of tumour suppressor genes in multistage chemical carcinogenesis. 184 54

Six families of activated protooncogenes, ras, raf, fur, neu, jun and myc have so far been associated with human lung cancer. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumour progression. When transferred into normal human bronchial epithelial cells by the highly efficient protoplast fusion method, the v-Ha-ras oncogene initiates a cascade of events leading to decreased responsiveness of these cells to inducers of squamous differentiation, aneuploidy and, less frequently, 'immortality' and tumorigenicity with metastasis in athymic nude mice. Transfection of the SV40 T antigen gene results in nontumorigenic cell lines that have a nearly normal pathway of terminal squamous differentiation and can be transformed into malignant cells by transfected Ha-ras, N-ras or Ki-ras. The combination of transfected c-myc and c-raf-1 also transforms human bronchial epithelial cells into neoplastic cells that exhibit some phenotypic traits found in small-cell carcinomas. These and other results indicate that proto-oncogenes dysregulate the pathways of growth and differentiation of human bronchial epithelial cells and play an important role in human carcinogenesis. Analyses of allelic deletion and somatic cell hybrids are being used to identify the chromosomal localization of tumour suppressor genes. We have examined 54 non-small-cell bronchogenic carcinomas with 13 polymorphic markers. Loss of heterozygosity was more frequent than among 23 squamous-cell carcinomas than among 23 adenocarcinomas or eight large-cell carcinomas. Loss of heterozygosity for chromosome 17p was found in 89% of cases of squamous-cell carcinoma and 18% of adenocarcinomas. Analysis of chromosome 11 for allelic deletions revealed two commonly deleted regions (11p13 and 11p15.5). Somatic cell hybrids between normal human bronchial epithelial cells and Hut292DM, a lung carcinoma cell line, had a finite lifespan in vitro and were nontumorigenic in athymic nude mice. Tumour suppressive effects of individual or combinations of specific human chromosomes on Hut292DM are being examined by formation of microcell-cell hybrids. Chromosome 11 has tumour suppressor activity in these hybrids. Both of these studies suggest that tumour suppressor genes play a dominant role in lung carcinogenesis and provide in-vitro model systems for isolating these genes by subtraction library and insertional mutagenesis techniques.
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PMID:Role of oncogenes and tumour suppressor genes in human lung carcinogenesis. 185 68

There are abnormalities in the structure and/or function of several oncogenes and growth factors in human pancreatic cancer, notably the EGF receptor and its ligand TGF alpha, c-erb B-2 proto-oncogene, Ki-ras oncogene and the tumour suppressor gene p53. The temporal sequence of their activation and the nature of the aetiological agents responsible for their activation are not yet clear. In vitro pancreatic culture systems and transgenic animal experiments are needed to reconstruct and define those molecular events that are necessary and sufficient for the neoplastic phenotype.
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PMID:Growth factors and oncogenes in pancreatic cancer. 196 2

Tumour and blood leucocyte DNA from a consecutive series of patients with primary breast cancer was probed to detect deletions at six polymorphic loci in tumour tissue. The highest frequency of allele loss (61%) was found with the probe YNZ22, which detects a sequence on the short arm of chromosome 17 (at p13.3). The previously reported loss of alleles at the Harvey ras locus (11p14) in about 20% of breast tumours was confirmed. The putative breast tumour suppressor gene on 17p may be the same as that already noted for colon and lung cancers and it is suggested that deletion of this gene is one of a cumulative series of lesions involving genetic changes in the evolution of breast cancer. The findings identify chromosome 17p as a candidate region for linkage studies in breast cancer families.
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PMID:Allele loss on short arm of chromosome 17 in breast cancers. 290 22


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