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)

Wild-type and mutant p53 proteins exhibit opposing activities in respectively suppressing and promoting tumour development. In a rat embryo fibroblast cell line transformed with a murine temperature-sensitive p53 gene, p53 functions as a oncogene at 37 degrees C and as a tumour suppressor at 32 degrees C [Michalovitz, D., Halevy, O. & Oren, M. (1990). Cell, 62, 671-680]. We have used this cell line to investigate whether this temperature-dependent switching of function involves changes in the phosphorylation of p53 protein. Monoclonal antibodies PAb246 and PAb240 were used to immunoprecipitate metabolically 32P-labelled p53 protein in the 'wild-type' or mutant conformation from cells grown at 32 degrees C or 37 degrees C. Tryptic phosphopeptide maps were prepared from the isolated 'wild-type' and mutant p53 proteins. At 32 degrees C and 37 degrees C phosphopeptide maps of the 'wild-type' and mutant protein were identical. This demonstrates that the temperature-dependent conformation change, and associated functional change, in the p53 protein does not involve a change in the state of phosphorylation.
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PMID:The conformational change of a murine temperature-sensitive p53 protein is independent of a change in phosphorylation status. 163 Aug 25

Colorectal tumours have proven to be an excellent system in which to identify and study the genetic alterations involved in the development of a common human neoplasm. A prevalent view is that colorectal tumours appear to arise as the result of multiple genetic alterations in the alleles of both oncogenes and tumour suppressor genes. The accumulation of genetic alterations appears to accompany the clinical and biological progression of the tumours and may determine the phenotype of the tumour cells. In addition to the many somatic alterations identified at various stages of colorectal tumour development, recent studies have led to the identification of the adenomatous polyposis coli (APC) gene, which, when mutated in the germline, predisposes to the development of colorectal tumours. On the basis of studies of inherited and somatic mutations in colorectal tumours, a genetic model for colorectal cancer development has been proposed. Although the model is undoubtedly incomplete, it nevertheless provides a useful framework for further studies of the multiple events that underlie human tumour initiation and progression. Numerous questions remain to be answered, including identification of the normal function of the genes implicated in tumorigenesis, how mutations in these genes arise and are selected for and what the relative contribution of the altered genes is to various stages of the neoplastic process. Nevertheless, an optimistic outlook is that fundamental insights into the pathogenesis of human cancer are within our reach.
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PMID:Genetic alterations underlying colorectal tumorigenesis. 163 44

The development of Friend virus induced murine erythroleukaemia is associated with specific genetic events. One of these events is loss of wild type p53 expression, which can occur by internal deletion or proviral insertion in the p53 gene and by single point mutations in the coding sequence. In all cases, the corresponding wild type allele is absent. The high frequency of observed p53 mutations strongly suggests that inactivation of p53 may be an obligatory step in the development of Friend disease. Further evidence that abrogation of normal p53 expression contributes to the development of malignant clones was provided by in vitro reconstitution experiments in Friend cell lines: whereas exogenous mutant p53 was stably expressed in p53 negative FCLs, long term wild type p53 expression was not detected. Friend erythroleukaemia arises as a late consequence of infection of susceptible mice with Friend virus. In addition to p53 gene mutations, proviral insertions occur frequently adjacent to one of two cellular genes, Spi-1/PU.1 or Fli-1. Aberrant expression of these genes may therefore be involved in virus induced erythroleukaemia. Interaction of SFFV env gp55 with the EPO-R also appears to be important in providing a mitogenic signal to infected cells. The order in which these events occur and whether the order is relevant to the progression of the disease are not known. Investigation of the stepwise appearance of these events could provide information on the possible interactions of the gene products involved. Abrogation of normal p53 expression is not restricted to Friend erythroleukaemia: the observation of p53 mutations and allele loss in human breast, lung, colon and hepatocellular carcinomas and in leukaemia suggests that mutation of p53 may be the most common genetic abnormality detected in human cancer (reviewed in this issue). Studies of p53 expression in FCLs provided an early indication that p53 was a tumour suppressor gene. Further studies of the mechanisms by which wild type and mutant p53 affect the growth of p53 negative FCLs may reveal important biochemical properties of p53 in relation to cell cycle control and differentiation of erythroid cells.
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PMID:Friend virus induced murine erythroleukaemia: the p53 locus. 163 45

Mutations of the p53 tumour suppressor gene have frequently been observed in several types of solid tumours and are believed to be implicated in the development of these tumours. To determine the relevance of p53 mutations in haematologic neoplasms, we performed polymerase chain reaction-single strand conformation polymorphism analysis on the p53 gene in 45 patients with various types of haematologic neoplasms. In exons 5-8 containing highly conserved regions, mobility shifts indicating sequence alterations were detected in four of the 45 patients, and subsequent sequencing was performed. A point mutation resulting in a novel stop codon was detected at codon 213 in one of 23 cases of chronic myelogenous leukaemia (one of five cases of blast crisis). Point mutations causing amino acid substitutions were detected in one of four cases of myelodysplastic syndrome at codon 195, one of three cases of adult T-cell leukaemia at codon 281, and one of eight cases of acute lymphoblastic leukaemia at codon 281, and these missense mutations were accompanied by loss of the wild type allele. Patients harbouring these nonsense and missense mutations were in advanced disease stages. These findings suggest that mutational inactivation of the p53 gene is infrequent but is involved in the tumorigenesis of several types of haematologic neoplasms at least in some cases.
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PMID:Mutations of the p53 tumour suppressor gene in haematologic neoplasms. 848 63

Tumour viruses are thought to contribute to the development of one fifth of all human cancers, although the mechanisms involved are still obscure. Human papilloma virus (HPV) is a DNA virus associated with oral carcinomas. It has been shown that virus DNA has to become integrated into cellular DNA in order to transform normal to malignant cells. Cellular oncogenes and tumour suppressor genes are potential cancer genes. They are involved in the control of growth and differentiation of normal cells. It is known that structural or regulatory changes (activation) of these genes will lead to malignant transformation. Virus integration will sometimes take place in close relation to cellular oncogenes. Such incorporation may result in oncogene activation. Other cellular factors that may contribute to the development of oral squamous cell carcinoma are also discussed.
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PMID:[Can virus cause oral cancers?]. 165 Apr 50

Wilms' tumour (WT), aniridia, genitourinary abnormalities and mental retardation form a symptom group (WAGR syndrome) associated with hemizygous deletions of DNA in chromosome band 11p13 (refs 1,2). However, it has not been clear whether hemizygosity at a single locus contributes to more than one phenotype. The tumour suppressor gene for Wilms' tumour, WT1, has been characterized: it is expressed at high levels in the glomeruli of the kidney, as well as the gonadal ridge of the developing gonad, the Sertoli cells of the testis and the epithelial and granulosa cells of the ovary, suggesting a developmental role in the genital system in addition to the kidney. We now report constitutional mutations within the WT1 genes of two individuals with a combination of WT and genital abnormalities as evidence of a role for a recessive oncogene in mammalian development.
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PMID:WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. 165 25

Retinoblastoma, the most common intraocular malignancy of children, has served as an important paradigm for understanding the events involved in neoplastic transformation. Much of the contemporary molecular description of human cancers stems directly from experimental approaches first developed to study this childhood tumour. This analytical methodology has demonstrated a major role for heritable predisposition in tumourigenesis, provided evidence for tissue pleiotropy of cancer genes, and revealed a more precise estimation of the number, activity, and location of other tumour suppressor loci.
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PMID:Molecular genetics in the pathology and diagnosis of retinoblastoma. 166 90

Development of colon carcinomas can be associated with allelic deletions on several chromosomes, including 5q and 18q. The APC gene on 5q and the DCC gene on 18q have been identified as potential tumour suppressor genes, whose suppression contributes to colon carcinogenesis. To investigate the role of genes in these deleted regions, we have now introduced a single normal human chromosome into a human colon carcinoma cell line, COKFu, through microcell hybridization. Several clones of hybrid cells containing normal chromosome 5, and others containing normal chromosome 18, were obtained. The morphology of the hybrid cells was markedly altered: the hybrids with chromosome 5 exhibited a closely packed polygonal morphology, and the hybrid cells with chromosome 18 were flattened. The cloning efficiency of the hybrid cells in soft agar was reduced from 0.46 to 0% of that of the parental carcinoma cells, and the tumorigenicity of these hybrid cells in athymic nude mice was completely suppressed. The growth properties of the hybrid cells with chromosome 11 were not substantially changed. These results strongly suggest that the genes on normal chromosome 5 and 18 function as tumour suppressors in colon carcinogenesis.
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PMID:Suppression of tumorigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. 167 Sep 65

We have examined a series of 13 benign and 27 malignant human gliomas for evidence of molecular abnormalities of proto-oncogene and putative tumour suppressor gene loci. The results indicated that specific molecular lesions were associated with increasing grades of malignancy. Thus, loss of genetic material on chromosome 17 was present with approximately equal frequency in both benign and malignant gliomas, whereas loss of loci on chromosome 10 was seen only in malignant gliomas. Only the most malignant tumours, known as glioblastoma multiforme, had more than one molecular abnormality in the same tumour. These findings may contribute to our understanding of glial tumour development, as well as improve the accuracy of tumour diagnosis.
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PMID:Multiple sequential molecular abnormalities in the evolution of human gliomas. 167 78

Recent studies have identified a gene on chromosome 5q, designated MCC (mutated in colorectal cancers), as a candidate for the putative colorectal tumor suppressor gene that is located at 5q21. We examined loss of heterozygosity (LOH) at the MCC locus and its vicinity in sporadic colorectal carcinomas, using 12 RFLP (restriction fragment length polymorphism) markers. One clone, L5.71, had been used to identify the MCC gene; all 12 markers also had tight linkage to the gene responsible for adenomatous polyposis coli. All 40 cases studied were informative with at least one marker, and 22 of them (55%) showed LOH at one or more loci. LOH in the tumors was more frequent in the immediate vicinity of L5.71 than in distant parts of the chromosome, and a common region of deletion was detected between markers L5.62 and 15A6. In one case, alleles were retained at L5.71 and at loci proximal to L5.71, but alleles were lost at loci distal to L5.71. In another case, both alleles were retained at L5.71 but alleles were lost at loci proximal and distal to L5.71. These results support the conclusion that a tumor suppressor gene for colorectal carcinoma is located within or around locus L5.71.
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PMID:Frequent loss of heterozygosity at the MCC locus on chromosome 5q21-22 in sporadic colorectal carcinomas. 168 92


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