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)

This historical survey has shown the emergence over a period of about 60 years of a coherent view of DNA-reactive carcinogens and their effects. The earliest workers, in the 'pre-Watson-Crick' era, probably thought that the mode of action of carcinogens, then largely comprising polycyclic aromatic hydrocarbons, would be revealed through a relationship to steroid hormones, and that they would have protein receptors. This may well apply, in a broad sense, to promoting agents in carcinogenesis. Demonstration of the mutagenicity of a chemical, mustard gas, shifted attention to alkylating agents as carcinogens, and to the concept of mutagens, carcinogens and cytotoxic agents as 'radiomimetic'. Alkylating carcinogens were shown to react with DNA in vitro and in vivo in ways consistent with their action as mutagens, particularly as inducers of base substitutions, GC-->AT transitions. Carcinogenic hydrocarbons were subsequently shown to react with DNA of their target tissue, mouse skin, to extents positively correlated with their carcinogenic potency. They were found to react through aralkylating metabolites to give products that can block DNA polymerase, but can also cause base substitutions of the transversion type, mainly GC-->TA. Current interest centres on correlating the observed base substitutions that activate oncogenes or inactivate tumour suppressor genes in human cancer with the nature of exogenous and endogenous mutagens and the chemistry of their reactions with DNA, in order to deduce whether specific carcinogens can be implicated in the etiology of cancers. Ancillary to these studies are determinations of carcinogen-DNA reaction products in DNA from human sources.
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PMID:From fluorescence spectra to mutational spectra, a historical overview of DNA-reactive compounds. 780 20

Abnormalities of the tumour suppressor gene p53 have been shown in approximately 60% of advanced gastric adenocarcinomas and it has been suggested that the immunohistochemical finding of increased p53 expression is a prognostic marker in gastric cancer. No studies of early (T1) tumours have been reported. Over expression of p53 protein in 95 early gastric carcinomas and in adjacent mucosa was investigated using immunohistochemistry with antibody CM1. Thirty five per cent of the tumours were positive. The frequency of p53 positivity in tumours of tubular histological type (46%) was significantly higher than that in signet ring tumours (10%) (p = 0.006), and neoplasms that invaded deeply into the submucosa were more frequently positive (45%) than others (30%). Five of eight (62%) T1 tumours with lymph node metastases showed immunoreactive p53. In signet ring tumours, immunopositivity correlated with the frequency of DNA aneuploidy. p53 Over expression was also found in 15% of 26 examples of high grade dysplasia in mucosa adjacent to invasive tumours. No positivity was found in intestinal metaplasia or in normal mucosa. The findings show that immunocytochemically demonstrable over expression of p53 correlates with other morphological markers of aggressiveness in T1 gastric adenocarcinoma. The increasing frequency of p53 immunoreactivity in the sequence of high grade dysplasia-->early gastric cancer-->advanced gastric cancer supports the view that abnormalities of p53 are related to tumour progression in gastric carcinogenesis.
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PMID:Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa. 782 4

Carcinogenesis is a multi-step process including aberrant expression of two interacting classes of genes--oncogenes and tumour suppressor genes. With recent technological advances, it is feasible to identify the various molecular lesions underlying the different stages of neoplasia. Squamous cell carcinomas of the head and neck, although representing 2-4% of the malignancies in the West, comprise a large fraction (40%) of total cancers in India, posing a major health problem. Further, epidemiological and experimental evidence unequivocally confirms a causal association between tobacco chewing habit, highly prevalent in India, and oral cancers. Thus, the oral cancers offer an excellent in vivo system for the study of the environmental tobacco-carcinogen induced molecular alterations in the malignancy, and associated premalignant lesions such as leukoplakia. With a view to elucidating the molecular lesions involving oncogenes in oral carcinogenesis, we have investigated myc/ras/EGF-R activation by amplification, point mutation, gene rearrangement and allelic losses. Further, a functionally activated potent transforming gene was detected in a NIH3T3 transfection/tumorigenicity assay, unrelated to myc/ras/EGF-R. Studies on the involvement of p53 gene in oral cancer, indicates p53 allelic loss as an event observed in leukoplakia and tumour tissues. Advanced oral cancer stages demonstrate cumulative molecular aberrations, with greater than 95% samples showing oncogene involvement, thus indicating a multi-step process of oral carcinogenesis. The review presents a comparative picture of the oral malignancies seen in Western countries and India, significance of molecular lesions and future perspectives of oncogenes and tumour suppressor gene involvement in oral cancer.
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PMID:Molecular lesions in human oral cancer: the Indian scene. 791 88

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

The MTS1/CDK4I gene encodes a 16 kDa cyclin kinase inhibitor and maps to chromosome 9p21. Previous studies have suggested the presence of a major tumour suppressor gene at this locus which may be inactivated in head and neck squamous cell carcinoma (HNSCC). To determine the status of this gene in human primary and metastatic HNSCC, we examined the locus and its transcript for abnormalities by polymerase chain reaction (PCR). Out of 14 cell lines studied, four had lost only exon 1, one had lost only exon 2, three had lost both exons 1 and 2, and none of the remaining six lines expressed a normal p16 mRNA. These latter six cell lines expressed p16 transcripts that had suffered deletions ranging in size from 2-16 base pairs. In each case, deletions led to a change of reading frame. Furthermore, in two cases abnormalities in the MTS1/CDK4I gene were identical in cells derived from metastatic tumours as compared to cells derived independently from the corresponding primary tumour. The identical nature of mutations observed in primary tumours and metastases derived from the same patient provides strong evidence that inactivation of p16 function was an in vivo event.
Carcinogenesis 1994 Dec
PMID:MTS1/CDK4I is altered in cell lines derived from primary and metastatic oral squamous cell carcinoma. 800 Dec 21

In 231 colorectal carcinomas, allele variation at four restriction fragments length polymorphisms (RFLP) loci on chromosome 17 have been studied by Southern analysis. Heterozygous loss of the TP53 gene was found in 68% (129/189) of the carcinomas informative on both chromosome arms. In 41% (77/189) of the carcinomas the loss was found only on 17p. Two probes were used to detect alterations on 17p, pBHP53 and pYNZ22. When loss was demonstrated with pYNZ22, pBHP53 also always showed loss (n = 45), whereas when loss was demonstrated with pBHP53, only 45 of 54 (83%) showed loss with pYNZ22. Loss on 17q was found in 34% (64/189) of the carcinomas, and 6% (12/189) had loss on this chromosome arm, only. Loss on 17q was significantly associated with loss on 17p (P < 0.01). These data confirm that the TP53 gene is the target of loss on chromosome arm 17p in colorectal carcinomas, and demonstrate that loss of the TP53 gene is most frequently part of limited, subchromosomal loss. Furthermore, the results do not suggest any additional tumour suppressor gene(s) on chromosome 17 involved in colorectal carcinogenesis.
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PMID:The TP53 tumour suppressor gene in colorectal carcinomas. I. Genetic alterations on chromosome 17. 809 8

We have shown elsewhere that highly non-uniform exposure to ionizing radiation from authentic Chernobyl-released and artificially-produced hot particles (fragments of nuclear fuel) transform fibroblastic 10T1/2 cells in vitro effectively. We have also shown that hot-particle exposure leads to mutation and overexpression of the tumour suppressor gene p53 (and some other growth-related genes) in mouse skin in vivo at a high frequency. In the present paper it is shown that hot-particles produced by irradiating natural uranium with slow neutrons, when implanted (immobilized) under the skin of hairless and nude mice, induce epidermal tumours in excess compared with the conventional non-threshold stochastic model of radiation-induced cancer. One explanation for the effectiveness of the hot-particle exposure, under the present assay conditions, is that the same cells in which specific radiation-induced DNA damage is most likely to occur, are forced into sustained mitotic activity in the chronic wound which develops around the radiation source (combined genotoxic and nongenotoxic effects). The results are consistent with a role for cell proliferation in multistage carcinogenesis in mouse skin.
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PMID:Tumour induction in mouse epidermal cells irradiated by hot particles. 809 89

Development of colon carcinomas appears to be associated with inactivation of multiple tumour suppressor genes. Cytogenetic and DNA analyses of colon carcinomas have detected a high frequency of chromosome 1p deletion, which suggests the presence of a tumour suppressor gene. We therefore introduced normal human chromosome 1 into colon carcinoma COKFu cells, through microcell hybridization. Six clones of hybrid cells containing normal chromosome 1 were obtained, four of which had a small fragment of the introduced chromosome 1, including 1p36-34. The morphology of hybrid cells with chromosome 1 markedly altered to a flat shape. The cloning efficiency of all six hybrid cells in soft agar was significantly reduced, and the tumourigenicity in athymic nude mice was completely suppressed. Hybrid cells containing only the region of 1p36-34, as well as those containing intact chromosome 1, showed suppressed transformed phenotype. Furthermore, several tumourigenic revertant cells were obtained from the hybrid cells. These revertant cells had a morphology similar to that of COKFu cells, and were found to have lost the 1p36 region from the introduced chromosome 1. These results indicate that a normal chromosome 1p36 carries a tumour suppressor gene for colon carcinogenesis.
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PMID:Suppression of tumourigenicity in human colon carcinoma cells by introduction of normal chromosome 1p36 region. 810 48

Solid tumours in man are characterized by acquired genetic rearrangements that, in most cases, can be detected by cytogenetic methods as clonal chromosomal abnormalities. Whereas primary abnormalities contribute to the establishment of the tumour and often are seen as solitary changes, secondary aberrations accrue during clonal evolution. Both abnormalities are nonrandom in distribution. Some primary abnormalities are so characteristic as to be virtually pathognomonic for particular types of solid tumours, eg, t (11;22)(q24;q12) in Ewing's sarcoma, t (9,22)(q22;q12) in extraskeletal myxoid chondrosarcoma, t (X;18)(p11;q11) in synovial sarcoma, and t (12;16)(q13;p11) in myxoid liposarcoma. To these purely cytogenetic data implicating specific genetic changes in carcinogenesis may now be added a growing evidence of molecular specificity emerging from recombinant DNA-studies. It appears that both currently known classes of directly cancer-relevant genes, the dominant oncogenes and the recessive tumour suppressor genes, are located at precisely those genomic sites that are visibly involved in neoplasia-associated chromosomal rearrangements. The importance of cytogenetic characterization of solid tumors is thus twofold. First, the recurrent aberrations provide insight into the pathogenetic mechanisms that are operative. They pinpoint areas of the human genome that carry genes or regulatory sequences whose function is disrupted in neoplastic cells. Second, even before the long-term goal of a more fundamental understanding of the neoplastic process is reached, the cytogenetic aberrations have direct clinical importance. The finding of an acquired clonal chromosomal abnormality identifies the presence of a neoplastic disease, and the specific type of aberration may reveal the true nature of the tumor and thus improve the diagnostic precision.
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PMID:[Significance of chromosomal abnormalities in solid tumors of humans]. 817 15


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