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)

Genes that can inhibit the expression of the tumorigenic phenotype have been detected by the fusion of normal and malignant cells, the phenotypic reversion of in vitro transformants, the induction of terminal differentiation of malignant cell lineages, the loss of 'recessive cancer genes', the discovery of regulatory sequences in the immediate vicinity of certain oncogenes, and the inhibition of tumour growth by normal cell products. Such tumour suppressor genes will probably turn out to be as, if not more, diversified as the oncogenes. Consideration of both kinds of genes may reveal common or interrelated functional properties.
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PMID:Tumour suppressor genes. 307 35

The inducible response of the tumour suppressor gene p53 has been examined following exposure to DNA-damaging agents in Ataxia telangiectasia (AT) cell lines, an autosomal recessive disorder with multiple clinical and biological abnormalities including sensitivity to ionising radiation. The p53 induction was significantly delayed and reduced in the 8 AT cell lines examined over the 6 h following irradiation with no dose response in p53 induction being observed compared to control cells. The increase of WAF1/CIP1(p21) and GADD45 mRNA, two genes transcriptionally activated by p53, was also reduced in the AT cell lines after such treatment. In contrast, the increase in p53 protein, WAF1/CIP1(p21) and GADD45 mRNA expression following exposure to the alkylating agent methylmethane sulphonate (25 and 100 micrograms ml-1) was similar in both cell types. No alterations in the expression of EBNA-5, an EBV-encoded nuclear antigen which has been shown to bind p53 or mutations in the p53 gene (exons 4 to 8) were found in the AT cell lines studied. The AT gene product would thus appear to be involved upstream of p53, GADD45 and WAF1/CIP1 (p21) in the signalling of the presence of strand breaks produced by ionising radiation, with this defect in response contributing to the high cancer risk and radiosensitivity observed in this disorder.
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PMID:The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. 747 67

The p21 gene encodes a cyclin-dependent kinase inhibitor that affects cell-cycle progression, but the potential of this gene product to serve as a tumour suppressor in vivo has not been established. In this report, we show that the growth of malignant cells in vitro and in vivo is inhibited by expression of p21. Expression of p21 resulted in an accumulation of cells in G0/G1, altered morphology, and cell differentiation, but apoptosis was not induced. Introduction of p21 with adenoviral vectors into malignant cells completely suppressed their growth in vivo and also reduced the growth of established pre-existing tumours. Gene transfer of p21 may provide a molecular genetic approach to arresting cancer cell growth by committing malignant cells irreversibly to a pathway of terminal differentiation.
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PMID:The p21 cyclin-dependent kinase inhibitor suppresses tumorigenicity in vivo. 748 53

Chromosomal deletions, associated with the loss of normal function of tumour suppressor genes, have been identified in a variety of both familial and sporadic human cancers. Although the molecular pathology of ovarian cancer is not understood, several studies have reported deletions in chromosome 17 in ovarian tumours. We have used 13 restriction site polymorphic, microsatellite, and variable number tandem repeat markers to make a detailed analysis of chromosome 17 deletions in 12 benign and 19 malignant ovarian tumours. Two benign and 11 malignant tumours were informative for at least one marker on each arm of the chromosome. Loss of heterozygosity (LOH) was detected in both arms (by all informative markers) in 5 malignant tumours from four women (three with the disease at FIGO stage Ia). In a further bilateral ovarian tumour a partial LOH affecting 17q22-q25 was present in one ovary only. By contrast to a number of previous studies, none of the 19 malignant and 12 benign tumours showed ERBB2 (17q12-22) amplification. The data presented show that the loss of a whole copy of chromosome 17 is a frequent and relatively early event in the development of some ovarian cancers. This suggests the possible involvement of multiple chromosome 17 loci in the pathogenesis of ovarian cancer. Equally plausible is that the loss of a whole chromosome copy could be the product of chromosomal instabilities induced by loss of the normal allele of tumour suppressors, such as TP53, located on this chromosome.
Genes Chromosomes Cancer 1993 Nov
PMID:Whole chromosome 17 loss in ovarian cancer. 750 29

The tumour suppressor gene, p53, has proved to be one of the genes most often modified in human cancers. These alterations consist mainly of point mutations located in the evolutionarily conserved sequences which render the protein inactive for its normal biological functions. In fact the p53 gene presents nearly 300 potential mutation sites whose analysis should enable the correlation of specific mutation spectra with different causal agents in cancer development. In this study we have analysed the mutation spectrum of the p53 gene in skin tumours from normal individuals and repair-deficient xeroderma pigmentosum (XP) patients in comparison with mutations found in internal cancers. Point mutations are mainly GC-->AT transitions in skin tumours (74% in non-XP, 87% in XP), and also to a lesser extent in internal tumours (47%) where, however, they are mainly located at CpG (63%) sequences probably due to the deamination of the unstable 5-MeC. Moreover, mutations are targeted at py-py sequences in over 90% of skin tumours whereas the distribution of mutations in internal malignancies is proportional to the frequency of py-py sites (61%) and other sequences (39%) at mutable sites. Indeed, in XP skin tumours 100% of the mutations are targeted at py-py sequences and 55% of these are tandem CC-->TT transitions considered as a signature of UV-induced lesions. In skin tumours from normal individuals, 14% of the p53 mutations are double mutations and as in XP skin tumours all these are CC-->TT transitions. In contrast, internal tumours rarely contain tandem mutations (0.8%), and of these only 2/14 were CC-->TT transitions. Finally, nearly all (95%) of the mutations in XP are located on the non-transcribed strand while internal or non-XP skin tumours do not show this strand bias. Hence, the mutation spectrum analysed in XP skin tumours also demonstrates for the first time the existence of preferential repair in humans. In conclusion, the specificity of UV-induced p53 mutation spectra in skin tumours shows that this gene is a particularly appropriate candidate for the correlation of mutation spectra with specific damaging agents.
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PMID:Can we predict solar ultraviolet radiation as the causal event in human tumours by analysing the mutation spectra of the p53 gene? 751 18

We have characterised a region of deletion on the long arm of chromosome 6 (6q) in six cases of acute lymphoblastic leukaemia, by fluorescence in situ hybridisation, using a series of YAC clones which map to 6q. Conventional cytogenetic analysis of four of these cases had been interpreted as showing terminal deletions of 6q. We demonstrated by FISH that in all cases the deletions were interstitial. D6S246 (6q16.3) was the only marker which was missing in all six cases, indicating a common region of deletion between the markers M6P1 at 6q14-15 and FYN at 6q21. Our results suggest the presence of a tumour suppressor gene within this interval.
Genes Chromosomes Cancer 1994 May
PMID:Deletion of a common region on the long arm of chromosome 6 in acute lymphoblastic leukaemia. 751 70

We have used fluorescence in situ hybridisation (FISH) with a series of yeast artificial chromosome (YAC) clones that map to the long arm of chromosome 6 (6q) to define the region(s) of deletion in seven cases of non-Hodgkin's lymphoma (NHL), in which a deletion of 6q had been detected by conventional cytogenetics. The FISH analysis detected two regions of deletion: (i) A proximal region flanked by M6P1 (6q14-15) and FYN (6q21), containing D6S246, which was missing in all seven cases. This locus was also found to be deleted in all six cases of acute lymphoblastic leukaemia (ALL) studied previously. (ii) A second region of 6q, which was distal to 6q23.1 (D6S238) and included ESR (6q25.1) and D6S281 (6q27), which was shown to be present in all our cases of ALL, was found to be deleted in 4 of the 7 cases of NHL. Our results support the suggestion that tumour suppressor genes, involved in the pathogenesis of lymphoid malignancies, may be present within these regions.
Genes Chromosomes Cancer 1994 Aug
PMID:Common region of deletion on the long arm of chromosome 6 in non-Hodgkin's lymphoma and acute lymphoblastic leukaemia. 752 44

Mutations in a human homologue of the yeast DNA mismatch repair gene MSH2 (equivalent to bacterial MutS) cause the condition hereditary non-polyposis colorectal cancer (HNPCC). Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Adenomas are clonal and each may serve as a marker of a single initiating mutation. The progression of adenomas is marked by increasing size, dysplasia and villosity. These characteristics can be taken as the morphological counterparts of the stepwise accumulation of mutations implicating oncogenes and tumour suppressor genes. The aim of this study was to link the morphogenesis of hereditary colorectal cancer with recent insights into the role of DNA mismatch repair genes. The frequency and anatomical distribution of adenomas in at-risk members of HNPCC families was the same as in an autopsy population. This suggests that the HNPCC gene does not initiate the process of neoplastic transformation. On the other hand, adenomas in at-risk members of HNPCC families were more likely to show villosity (p < 0.001), high grade dysplasia (p = 0.002) and probably increased size (p = 0.15). These findings are consistent with the observation that the HNPCC gene causes DNA replication errors to develop and accumulate within neoplastic but not normal tissues. The effect of the HNPCC gene is to accelerate the progression of adenoma to carcinoma, but not to initiate adenoma development.
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PMID:Hereditary non-polyposis colorectal cancer--morphologies, genes and mutations. 752 76

The mapping of the naevoid basal cell carcinoma syndrome (NBCCS) and the Ferguson-Smith syndrome to the same region on chromosome arm 9q has led to speculation that the two conditions may reflect different mutations within the same gene. Loss of heterozygosity of 9q alleles in both familial and sporadic basal cell carcinomas (BCCs) suggests that the NBCCS gene on 9q is acting as a tumour suppressor gene. Although LOH of 9q markers has not been studied in squamous cell neoplasms from patients with the Ferguson-Smith syndrome, chromosome 9 allele loss has been reported in sporadic squamous cell carcinomas (SCCs) of the skin. In order to characterise further the deleted region on chromosome 9 in BCCs and SCCs of the skin we have examined a series of non-melanoma skin cancers using a panel of highly informative microsatellite markers. Forty-four BCCs and 49 SCCs were studied. Loss of heterozygosity of one or more 9q markers was seen in 33 of the 44 BCCs. Only 4 of the 33 BCCs with 9q loss showed loss of 9p markers. Twenty-two BCCs showed loss of all informative 9q markers. Partial or interstitial 9q deletions were seen in 5 BCCs, and in 3 of these 5 BCCs the breakpoint occurred within the currently defined NBCCS locus. Chromosome 9 loss was seen in 16 of 49 SCCs. In contrast to the low frequency of 9p loss in BCCs, LOH of 9p markers was a common finding in SCCs, occurring in 15 of the 16 SCCs with chromosome 9 loss. In 5 SCCs 9p loss occurred with retention of 9q alleles.(ABSTRACT TRUNCATED AT 250 WORDS)
Genes Chromosomes Cancer 1994 Dec
PMID:Delineation of two distinct deleted regions on chromosome 9 in human non-melanoma skin cancers. 753 25

Angiogenesis is the development of new blood vessels from an existing vascular bed. Normal vascular proliferation occurs only during embryonic development, the female reproductive cycle and wound repair. By contrast, many pathological conditions (for example, cancer, atherosclerosis and diabetic retinopathy), are characterized by persistent, unregulated angiogenesis. Conversely, inadequate angiogenesis can lead to failure of ulcers to heal and myocardial infarction. Control of vascular development could permit new therapeutic approaches to these disorders. For example, several anti-angiogenic drugs are currently undergoing clinical trials for the treatment of cancer, whereas enhancement of angiogenesis by exogenous growth factors can prevent or limit the damage in chronic wounds and duodenal ulcers. Here Tai-Ping Fan, Rhys Jaggar and Roy Bicknell highlight recent achievements and discuss the prospects of receptor antagonists, enzyme inhibitors, tumour suppressor genes and vascular targeted approaches, especially that of gene therapy, in the future development of angiotherapy.
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PMID:Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. 753 71


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