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)

The p53 tumour suppressor gene is the most widely mutated gene in human tumorigenesis. p53 encodes a transcriptional activator whose targets may include genes that regulate genomic stability, the cellular response to DNA damage, and cell-cycle progression. Introduction of wild-type p53 into cell lines that have lost endogenous p53 function can cause growth arrest or induce a process of cell death known as apoptosis. During normal development, self-reactive thymocytes undergo negative selection by apoptosis, which can also be induced in immature thymocytes by other stimuli, including exposure to glucocorticoids and ionizing radiation. Although normal negative selection involves signalling through the T-cell receptor, the induction of apoptosis by other stimuli is poorly understood. We have investigated the requirement for p53 during apoptosis in mouse thymocytes. We report here that immature thymocytes lacking p53 die normally when exposed to compounds that may mimic T-cell receptor engagement and to glucocorticoids but are resistant to the lethal effects of ionizing radiation. These results demonstrate that p53 is required for radiation-induced cell death in the thymus but is not necessary for all forms of apoptosis.
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PMID:p53 is required for radiation-induced apoptosis in mouse thymocytes. 847 14

Central nervous system (CNS) tumours are the most common solid tumours in children. Cytogenetic and molecular genetic studies of these neoplasms have previously shown abnormalities of chromosome 17, implicating genes on this autosome in tumorigenesis. To identify mutations in the TP53 tumour suppressor gene (17p13.1), we have sequenced the five highly conserved regions of this gene in 29 mixed paediatric CNS tumors. No mutations were detected by this analysis. In order to identify other candidate disease loci on chromosome 17, we have carried out a detailed deletion mapping analysis using 16 polymorphic DNA markers on 19 of the above tumours and an additional four cases. Abnormalities of chromosome 17 occurred in nine cases (39%), six of which were primitive neuroectodermal tumour (PNET)-medulloblastomas. These findings suggest that it is unlikely that the TP53 gene is directly involved in the development of common paediatric brain tumours. This is in contrast to findings from adult brain and other tumour types. Moreover, the frequency of chromosome 17 aberrations, especially in PNET-medulloblastomas, suggests that other genes on this chromosome contribute to tumourigenesis.
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PMID:Chromosome 17 abnormalities and lack of TP53 mutations in paediatric central nervous system tumours. 852 28

Epithelial tumours develop through a sequence of pre-invasive lesions of increasing disarray driven by underlying somatic genetic changes. We have studied the occurrence of the two most common somatic genetic changes associated with lung cancer in a series of premalignant bronchial lesions representing different stages in lung tumorigenesis. We present evidence that allele loss on chromosome 3 precedes damage to the p53 gene. Damage to chromosome 3 itself appears to be sequential in that the pattern of allele loss seen in dysplasia is often much more discrete than in invasive tumours. This implies that preneoplastic lesions may be a useful source of material for deletion mapping studies aimed at localising the position of tumour suppressor genes. We illustrate this by the comparison of an interstitial deletion described in this study with a homozygous deletion we have described previously, which has resulted in a better definition of the localisation of a tumour suppressor gene believed to be involved in lung cancer development.
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PMID:Sequential molecular genetic changes in lung cancer development. 854 16

Chromosome 3p allele loss is frequent in ovarian and testicular tumours. The von Hippel-Lindau (VHL) disease tumour suppressor gene maps to chromosome 3p25. Gonadal tumours may occur in patients with VHL disease, so somatic VHL gene mutations might be involved in the pathogenesis of sporadic gonadal tumours. To investigate this hypothesis, we screened 60 gonadal tumours (36 ovarian and 24 testicular) for VHL gene mutations and chromosome 3p allele loss. Although 38% (10/26) of informative ovarian and 54% (7/13) of testicular tumours demonstrated 3p allele loss, no somatic VHL gene mutations were detected in the 60 gonadal tumours analysed. This suggested that chromosome 3p tumour suppressor gene(s) other than VHL are involved in gonadal tumorigenesis.
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PMID:Molecular genetic analysis of the von Hippel-Lindau disease (VHL) tumour suppressor gene in gonadal tumours. 865 74

BRCA1 is a putative tumour suppressor gene located on chromosome 17q21. It spans 100kb of genomic DNA and encodes a protein of 200kD consisting of 1863 amino acids. Sixty-three distinct germline mutations of BRCA1 have now been identified in more than 100 patients with breast and/or ovarian cancer. These mutations are distributed across the entire coding region of the BRCA1 gene, and the majority (87%) are predicted to result in truncated proteins or loss of a BRCA1 transcript. No somatic mutations of the BRCA1 gene have been identified in sporadic breast cancers, though five mutations have been found in sporadic ovarian tumours. This suggests that mutations in the BRCA1 gene may play a significant role in the tumorigenesis of familial breast cancer but not of sporadic breast cancer.
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PMID:Mutations of the BRCA1 gene in human cancer. 869 65

A number of distinct strategies have been used over the past two decades to uncover the genes involved in tumorigenesis. Their use raises the questions of whether we will require novel approaches in order to continue the progress of cancer genetics. Retrovirus mediated transduction of proto-oncogenes and transfection of tumour associated oncogenes are both inefficient ways of uncovering oncogenes, each being encumbered by technical obstacles that limit their utility. Improvements in the gene transfer strategy may yield a host of new oncogenes. New cloning techniques may have a role here as well as in revealing the existence of genes that are amplified in tumour cell genomes. The major technique for uncovering novel tumour suppressor genes--detection of loss of heterozygosity--is also limited in its sensitivity to detecting genes that are lost in large numbers of tumours. The techniques for uncovering these genes through analysis of pedigrees in which mutant versions of these genes are passed through the germline are encumbered by issues of penetrance and the complexities associated with the inheritance of polygenic traits. In both instances, improvements in data acquisition and analysis will reveal tumour suppressor genes that have proved elusive until now. Over the next decade, we will learn much about how the defects in another apparatus--that responsible for the maintenance of genomic integrity--contribute to cancer susceptibility. Beyond these genes lie yet others about which we seem to know little at present--those that induce the last stages of cancer including invasiveness and metastasis. These will represent an entirely new cohort of genes to be uncovered over the next decade.
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PMID:Prospects for cancer genetics. 871 10

Transgenic mice expressing various oncogenes have been generated and widely used to study their role in tumorigenesis. The development of targeted mutagenesis allows specific genes to be mutated in mouse embryonic stem cells, which can then be used to generate mice with a germline mutation in that gene. Embryonic stem cell technology has been used to reconstruct genetic lesions in tumour suppressor genes such as p53 and Rb1, originally identified from studies in humans. The tumour susceptibility phenotype of mutant mice has unveiled the tumour suppressor activity of specific genes that were not expected to have such a function. Transgenic and knock out mice will have an increasingly important role in the identification of novel tumour suppressor genes.
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PMID:Role of transgenic mice in identification and characterization of tumour suppressor genes. 871 16

Molecular genetic analysis of breast cancers indicates that the mechanisms underlying tumorigenesis are complicated. Many oncogenes and tumour suppressor genes have been implicated, encoding proteins that are important at many levels of cell regulation, from cell surface molecules responding to external signals (eg ERBB2) to nuclear factors controlling gene transcription (eg TP53, MYC). Several correlations have been found between certain genetic events and clinical outcome and have therefore proved useful prognostic indicators. The mapping and cloning of genes important in familial breast cancers (eg BRCA1) have provided the essential tools for pinpointing the genes that may be critical in early stage breast cancer as well as for developing genetic tests for predicting carrier status in breast cancer families. Clarification of the molecular consequences of mutation in breast cancer associated genes is beginning to address the factors that drive a normal breast cell to change into a breast cancer cell. However, these studies are still in their infancy, and considerable research will be required to complete the picture.
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PMID:Molecular genetics of sporadic and familial breast cancer. 871 25

We analyzed seven cases of anaplastic ependymoma, focusing on neuro-imaging, histopathology, and mutations of the tumour suppressor gene p53. Five of the seven tumours were supratentorial. All had both cystic and solid components, with fragment calcifications detectable on CT scan. The solid parts of the tumours were imaged as heterogenous hypo- or iso-intense areas with moderate enhancement on T1-weighted magnetic resonance images. Vascularity was not prominent on angiograms except for one case. Histologically, in addition to the WHO criteria, loss of typical cellular architecture, endothelial proliferation, and necrosis were commonly found. A mutation in Exon 5 of the tumour suppressor gene p53 was detected in one anaplastic ependymoma out of five tumours (two benign and three anaplastic ependymomas) examined by PCR-SSPC analysis of genomic DNA followed by direct sequencing. Anaplastic ependymoma typically presents as a calcified cystic tumour in the supratentorial parenchyma or transependyma. Mutations of p53 deserve further investigation to examine their possible role in the oncogenesis and malignant transformation of ependymoma.
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PMID:Anaplastic ependymomas: clinical features and tumour suppressor gene p53 analysis. 874 9

1. Overexpression of the c-myc oncogene is associated with a variety of both human and experimental tumours, and cooperation of other oncogenes and growth factors with the myc family are critical in the evolution of the malignant phenotype. 2. Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promoter-human transforming growth factor (TGF-alpha) cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing the interaction of nuclear oncogenes and growth factors in tumourigenesis. 3. Coexpression of c-myc and TGF-alpha as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumours were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. 4. These observations suggest that the interaction of c-myc and TGF-alpha, during development of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases the probability of malignant conversion. 5. We have now extended these studied and examined the interaction of hepatocyte growth factor (HGF) with c-myc during hepatocarcinogenesis in the transgenic mouse model. While sustained overexpression of c-myc in the liver leads to cancer, coexpression of HGF and c-myc in the liver delayed the appearance of preneoplastic lesions and prevented malignant conversion. Similarly, tumour promotion by phenobarbitone was completely inhibited in the c-myc/HGF double transgenic mice whereas phenobarbitone was an effective tumour promoter in the c-myc single transgenic mice. 6. The results indicate that HGF may function as a tumour suppressor during early stages of liver carcinogenesis, and suggest the possibility of therapeutic application for this cytokine. Furthermore, we show for the first time that interaction of c-myc with HGF or TGF-alpha results in profoundly different outcomes of the neoplastic process in the liver.
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PMID:Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis. 880 43


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