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)

Thyroid tumorigenesis is discussed in the context of the thyroid as a stable tissue, composed of differentiated cells, with a greater dissociation of control of growth from control of differentiation than is found in stem cell tissues. Experimental thyroid carcinogenesis regimes usually use mutagen exposure followed by induced growth. The normal thyroid follicle cell has a limited growth capacity, so loss of one tumour suppressor gene followed by growth-associated loss of heterozygosity would allow escape from this growth limitation, and the formation of a neoplastic clone. In man, there are two pathways of tumour formation, one through follicular adenoma to follicular carcinoma, and one to papillary carcinoma. These two pathways show differing aetiology, and differing oncogene involvement. In the follicular carcinoma pathway TSH-induced growth is relevant as it is in experimental animals. Mutagenesis is important for both papillary and follicular carcinomas. Radiation mutagenesis is of particular current importance because of the occurrence of thyroid carcinoma in children exposed to fallout from Chernobyl. The greater capacity for post-mutagen growth in children than adults is likely to explain the increased radiosensitivity of children, both to external and internal radiation.
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PMID:Thyroid tumorigenesis. 795 31

The p53 tumour suppressor gene is an important participant in the cellular response to ionizing radiation and other DNA damaging agents. Cells which lack p53 are unable to arrest cell cycle or enter into apoptotic cell death following irradiation. Moreover, these p53 deficient cells exhibit an increased resistance to DNA damaging agents, including radiation. The significance of this radiation-resistance and its relationship to the role that p53 plays in tumour suppression and the cellular radiation response has not yet been determined. In this report we have analyzed p53 deficient mice, expressing either a mutant p53 transgene or having a targeted p53 null allele, in order to investigate the role that p53 plays in governing susceptibility to radiation-carcinogenesis and in controlling the in vivo accumulation of chromosomal abnormalities. We show that wild-type p53 plays a critical role in controlling susceptibility to gamma-radiation-induced tumorigenesis, and sarcomas and lymphomas rapidly appear in irradiated p53 transgenic mice. Moreover, this susceptibility to radiation-carcinogenesis is associated with a two-fold increase in the in vivo accumulation of radiation-induced double stranded chromosomal breaks relative to that observed in wild-type animal. Taken together, these observations suggest that p53 acts to suppress tumour formation in vivo by preventing the accumulation of cells that have sustained radiation-induced DNA damage.
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PMID:Susceptibility to radiation-carcinogenesis and accumulation of chromosomal breakage in p53 deficient mice. 797 Jul 33

Transgenic mice were generated which express a truncated nuclear retinoic acid receptor beta (RAR beta), closely resembling the natural isoform RAR beta 4, under the control of the MMTV promoter. The transgene was expressed in salivary gland, testis, lung and mammary tissue in two different lines. At approximately 11-14 months virtually all the transgenic mice showed hyperplasia of the lung alveolar epithelium with an excess of type II pneumocytes. Hyperplasia of the mammary alveoli and terminal ducts was also seen in some females. Salivary glands and some sebaceous glands were hyperplastic in most male transgenic mice, but only rarely in females or in non-transgenics. Primary benign and malignant tumours were more numerous in transgenic mice than in controls, with a total of 23 in 43 mice versus two in 33 non-transgenic animals. Treatment with dexamethasone to increase transgene expression resulted in exaggerated versions of the above phenotypes. Overexpression of RAR beta 4 therefore appears to predispose various tissues to hyperplasia and neoplasia, and this by contrast to the RAR beta 2 isoform, which has tumour suppressor activity. A survey of ratios of RAR beta 4:RAR beta 2 expression in human lung tumour cell lines showed an increase compared with normal lung tissue, suggesting that RAR beta 4 may play a similar role in human tumorigenesis.
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PMID:Hyperplasia and tumours in lung, breast and other tissues in mice carrying a RAR beta 4-like transgene. 798 54

Karyotypic analysis, loss of somatic heterozygosity, microcell fusion and cDNA transfection studies have provided compelling evidence that at least one tumour suppressor gene for melanoma resides on chromosome 6. In an attempt to further define the regions to which these putative suppressor genes map, we have carried out loss of heterozygosity (LOH) studies on DNA from 25 fresh melanoma tumours for 9 simple tandem repeat (STR) polymorphism markers spanning chromosome 6. Four samples displayed LOH or homozygosity for all markers studied, indicating that they had lost one homologue of chromosome 6. An additional 3 samples showed LOH for all markers on 6q. Furthermore, 30 melanoma cell lines, for which there were no matching somatic DNA samples, were analyzed for hemizygosity of markers on 6q. One cell line had a homozygous deletion of all markers tested and a further 12 cell lines displayed only one allele for 3 or 4 contiguous markers, indicating that most, if not all of these samples were hemizygous for the region of 6q distal to D6S87. Overall, the rate of LOH on 6q in the 55 melanoma DNAs was 35%, and there were no losses of markers on 6p without concomitant loss of markers on 6q. Two of 5 samples derived from primary melanomas showed LOH, which indicates that LOH for the melanoma suppressor gene on 6q, which maps to a region that contains the SOD2 locus, is a frequent and early event in melanoma tumorigenesis.
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PMID:Simple tandem repeat allelic deletions confirm the preferential loss of distal chromosome 6q in melanoma. 802 82

The first human tumour suppressor gene, the Retinoblastoma Susceptibility gene (RB1) was first demonstrated in retinoblastoma, a rare paediatric eye tumour which has been studied extensively over the last century. Genetic studies of retinoblastoma have yielded unique insights into familial cancer syndromes and the mechanisms of oncogenesis by tumour suppressor genes such as the RB1 gene. In this view, we will summarize past research into the genetics of retinoblastoma that led to the discovery of the RB1 gene and discuss the influence these results have had on the field of cancer research. In addition, we will discuss current research into RB1 as it relates to cancer and its potential for new therapies.
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PMID:The retinoblastoma gene and its significance. 807 36

Expression of the E-cadherin cell adhesion molecule is reduced in several types of human carcinomas, and the protein serves as an invasion suppressor in vitro. To determine if mutations of the E-cadherin gene (on chromosome 16q22) contribute to epithelial tumorigenesis, 135 carcinomas of the endometrium and ovary were examined for alterations in the E-cadherin coding region. Four mutations were identified: one somatic nonsense and one somatic missense mutation, both with retention of the wild-type alleles, and two missense mutations with somatic loss of heterozygosity in the tumour tissue. These data support the classification of E-cadherin as a human tumour suppressor gene.
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PMID:Mutations of the E-cadherin gene in human gynecologic cancers. 807 49

The neurofibromatosis 2 gene (NF2) has recently been isolated and predicted to encode a novel protein related to the moesin-ezrin-radixin family of cytoskeleton-associated proteins. Here we describe a novel isoform of the NF2 transcript that shows differential tissue expression and encodes a modified C terminus of the predicted protein. Mutations affecting both isoforms of the NF2 transcript were detected in multiple tumour types including melanoma and breast carcinoma. These findings provide evidence that alterations in the NF2 transcript occur not only in the hereditary brain neoplasms typically associated with NF2, but also as somatic mutations in their sporadic counterparts and in seemingly unrelated tumour types. The NF2 gene may thus constitute a tumour suppressor gene of more general importance in tumorigenesis.
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PMID:Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumour types. 816 73

p53 is now well characterized as a tumour suppressor gene, with loss of normal p53 function being recorded as the commonest genetic event associated with human malignancy. In particular, its involvement with tumorigenesis within the intestine is well established. Normal p53 function has been shown to be crucial for the induction of apoptosis in tumour cell lines, murine thymocytes and murine haematopoietic cells following DNA damage. To elucidate further the role of p53 in the cellular response to DNA damage we have investigated the response to gamma-irradiation of crypt cells in vivo from the small and large intestine of mice bearing a constitutive p53 deletion. Four hours after gamma-irradiation, a time point at which wild type crypt cells show abundant apoptosis, crypt cells from p53-deficient mice differed in that they were completely resistant to the induction of apoptosis. The p53 dose dependence of this phenomenon was clearly shown by the intermediate level of apoptosis observed in p53 heterozygotes. Analysis of the mitotic index and the bromodeoxyuridine labelling index showed that two other responses of wild type crypts to gamma-irradiation, namely the G2 block and the reduction in bromodeoxyuridine incorporation, were both largely intact in p53 deficient animals. These observations demonstrate that p53 function is essential for a major component of the normal response to gamma-irradiation induced DNA damage in intestinal mucosal cells, and suggest that p53 deficiency permits a population of cells bearing DNA damage to escape the normal process of deletion.
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PMID:p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following gamma-irradiation. 818 75

It is estimated that the hereditary polyposis and non-polyposis colorectal cancer (CRC) syndromes, which have an autosomal dominant pattern of inheritance, represent less than 10% of the total CRC burden. Thus, more than 90% of all cases of CRC have previously been considered to arise 'sporadically', with no identifiable genetic link. However, recent clinical evidence now suggests that a significant proportion of CRC seen in the general population may involve an inherited genetic susceptibility. Therefore, constructing an accurate family tree on all patients with a family history of CRC is an essential part of identifying families with an increased risk for CRC who could then be offered screening. Also, molecular genetic study of colorectal adenomas and carcinomas has led to a proposed genetic model of colorectal tumorigenesis which involves interactions between oncogenes and tumour suppressor genes. This information has important potential implications for screening, determining prognosis and for providing multiple targets for altering the sequence of malignant transformation.
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PMID:Heredity, molecular genetics and colorectal cancer: a review. 829 11

Alterations of the p53 tumour suppressor gene are considered critical events in multistage carcinogenesis of a wide range of human cancers. In an attempt to elucidate the role of various p53 mutations in tumorigenesis and to investigate their relationship to the p53 protein accumulation and subcellular localization, we have raised a new series of 21 mouse monoclonal antibodies (MAbs) to human recombinant p53. The new MAbs (designated the Bp53 series) appear to recognize mainly denaturation-resistant epitopes in immunoblotting and the majority of them are suitable for immunostaining of p53 in cultured cells and frozen sections. Furthermore, at least three MAbs (Bp53-11, Bp53-12, and Bp53-28) proved to be reliable reagents for immunohistochemistry on paraffin-embedded specimens. The immunohistochemical analysis of paraffin sections from 118 human tumours of various histogeneses with Bp53-11 and Bp53-12 showed nuclear accumulation of the p53 protein in variable proportion of tumour cells in 76 cases (64 per cent). The influence of three parameters of tissue processing (type of fixative, period of fixation, and duration of autolysis) on p53 protein detection was also investigated. The results of this study provide the necessary basis for wider application of these novel MAbs as tools in both routine histopathology and functional analyses of the p53 oncoprotein.
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PMID:Immunohistochemical analysis of the p53 oncoprotein on paraffin sections using a series of novel monoclonal antibodies. 843 13


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