Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific transfer of normal chromosomes via microcell fusion has been instrumental in identifying putative tumor suppressor gene loci in a variety of human cancers. Using this same technique it has been proposed that the tumorigenicity of the human fibrosarcoma cell line HT1080 is controlled by functionally distinct tumor suppressor genes on human chromosomes I and II. To address these results and perhaps further localize the suppressive effect to particular regions on these two chromosomes, we transferred into HT1080 seven different fibroblast-derived human chromosomes containing either intact or discrete portions of chromosome I or II. Interestingly, we found no evidence of genes on these chromosomes that could alter the growth of HT1080 either in vitro or in vivo. Based on these results we were left with the possibility that a gene, or genes, residing on an entirely different chromosome(s) was involved in the tumorigenesis of HT1080. Since TP53 mutation has been documented in a variety of human tumor types, and we found both copies of TP53 to be mutated in HT1080, we were prompted to examine its role by both cDNA transfection and chromosome transfer. Although by cDNA transfection we found that expression of exogenous wild-type TP53 was incompatible with continued proliferation of HT1080 cells in vitro, chromosome 17 transfer studies revealed that a more physiologic expression of exogenous wild-type TP53 could be tolerated in vitro while being completely incompatible with growth in vivo. These studies demonstrate a differential effect of TP53 growth inhibition and clearly show that TP53 tumor suppressing function can be independent from its potent growth suppressing effect in vitro.
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PMID:Evidence that wild-type TP53, and not genes on either chromosome 1 or 11, controls the tumorigenic phenotype of the human fibrosarcoma HT1080. 751 49

To investigate genetic features of esophageal cancer, we have examined 93 squamous cell carcinomas of the esophagus for loss of heterozygosity (LOH), using 41 restriction fragment length polymorphism (RFLP) markers representing all autosomal chromosomes. Allelic losses at frequencies of at least 30% were observed at loci on chromosomal arms 3p (35%), 3q (30%), 5q (36%), 9p (57%), 9q (60%), 10p (33%), 13q (43%), 17p (62%), 17q (46%), 18q (38%), 19q (32%), and 21q (37%). These results suggest that several putative tumor suppressor genes, in addition to the cyclin D and TP53 genes that are sometimes mutated in esophageal carcinomas, may be associated with development and/or progression of esophageal cancer. By a comparison of LOH on each chromosomal arm with clinicopathological parameters, we have found a significant correlation between LOH on 19q and regional lymph node metastases. Interestingly, the frequency of LOH on 17q was significantly higher in tumors in female patients (12 of 14 cases) than in those in male patients (20 of 56 cases) (P = 0.0009 by Fisher's exact test). Furthermore, we examined for mutations of the APC gene on chromosome arm 5q. Screening of nearly one third of the APC coding region, including the MCR (mutation cluster region), revealed no alterations. Therefore, although allelic loss at the APC locus is frequent in squamous cell carcinomas of the esophagus, it is likely that a gene on 5q other than APC is involved in esophageal tumorigenesis.
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PMID:Allelotype study of esophageal carcinoma. 752 40

Accumulation of mutations in oncogenes and tumor suppressor genes transforms a normal cell into a malignant cell by allowing it to escape from normal control of growth. In prostate tumorigenesis, the current model envisages specific mutations of the TP53 tumor suppressor gene and loss of loci, detected by loss of heterozygosity (LOH), on chromosome arms 8p, 10q, 16q, and 18q. In order to determine if alterations frequently found in other adenocarcinomas (breast, ovarian, gastric, colorectal), including losses of genetic material from chromosome arms 1p, 3p, 7q, 8p, 11p, 17p, 17q, and 18q, are also involved in prostate cancer, we examined 20 localized early-stage prostate tumors. We detected no mutations of the TP53 gene. Allelic losses were found from 7q (33%), 8p (50%), 10q (20%), and 18q (33%). Furthermore, as the first step toward isolating tumor suppressor genes on 18q, we used six polymorphic markers and identified a small common deleted region between the chromosome 18 centromere and the D18S19 locus.
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PMID:Genetic alterations in localized prostate cancer: identification of a common region of deletion on chromosome arm 18q. 752 48

Using the thyroid as a model of multistep epithelial tumorigenesis, we have used representative cell lines to correlate the degree of malignant transformation with the functional status of p53 and the integrity of cell-cycle check-points. Three distinct phenotypes were observed: Type I lines, derived from poorly-differentiated human thyroid cancers, expressed high levels of mutant p53 protein; Type II, also poorly-differentiated but derived from rat, showed over-expression of wild-type (wt) p53 with marked cell-cell heterogeneity: Type III, from well-differentiated human cancers, contained uniformly low levels of wt p53. All cell lines containing wt p53 retained a near-normal induction of p53 by DNA damage. However, the ability to undergo growth arrest differed strikingly. Whereas Type I and II lines had lost both G2/M and G1/S check points, Type III cells retained both. In Type III cells, as in diploid human fibroblasts, mutant p53 expression specifically abrogated G1/S check-point function with no other change in phenotype. These data demonstrate 3 mechanisms for evasion of p53 growth control: (i) direct mutation (ii) indirect inactivation, or (iii) 'avoidance' of activation, most probably due to failure to reach a critical threshold of DNA damage.
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PMID:Evasion of p53-mediated growth control occurs by three alternative mechanisms in transformed thyroid epithelial cells. 752 18

Colorectal tumorigenesis evolves through a series of molecular genetic changes, providing putative markers for tumour progression. This study investigated the relation between expression of the tumour suppressor gene p53 and splice variants v5 and v6 of the cell adhesion molecule CD44 by immunohistochemistry on tissue samples of early adenomas (n = 12), late adneomas (n = 12), Dukes's A and B carcinomas (n = 21), and Dukes's C and D carcinomas (n = 22) and compared these results with expression of these proteins in normal colonic mucosa (n = 17). A statistically significant trend of increasing expression was seen for both p53 (p < 0.005) and CD44 variant exon v6 (p < 0.0005) in subsequent stages of this tumour progression model. High expression of CD44 v5 was seen in most colorectal neoplasms (83%-96%), independent of stage. A statistically significant correlation was present between p53 expression and expression of variant v6 of CD44 (p < 0.01). Both p53 expression and CD44 v6 expression in adenomas increased with the degree of dysplasia (p < 0.05). The results of this study show that mutant p53 protein and variant v6 of the CD44 glycoprotein are markers of tumour progression in colorectal cancer.
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PMID:Expression of mutant p53 protein and CD44 variant proteins in colorectal tumorigenesis. 754 Oct 11

Transgenic mice that expressed v-fos exclusively in the epidermis by means of a human keratin K1-based targeting vector (HK1.fos) developed preneoplastic epidermal hyperplasia and hyperkeratosis after long latency and an associated wound promotion stimulus. To assess the requirements for papilloma formation and malignant conversion and determine the sensitivity to a chemical promotion stimulus, HK1.fos mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). HK1.fos mice were sensitive to TPA promotion but developed papillomas only after long latency (20-30 weeks of promotion) and in relatively few numbers per animal, suggesting the necessity of an additional genetic event prior to overt lesion formation. Consistent with this idea, at 60 weeks, on cessation of TPA promotion, these HK1.fos TPA-papillomas were found to be autonomous, TPA-independent tumors which persisted, grew larger, and converted to malignancy. Analysis of HK1.fos tumor RNA and DNA identified endogenous c-rasHa mutations at codons 12 and 61 in papillomas and carcinomas; however, no p53 tumor suppressor gene mutations were detected. These data indicate that epidermal expression of v-fos induces sensitivity to TPA promotion, but since additional genetic events, such as endogenous c-rasHa activation, appear to be required in tumorigenesis, v-fos may predominantly play a role in the mechanism of promotion to achieve papilloma autonomy and TPA independence. Furthermore, spontaneous malignant conversion in this model does not appear to involve mutations in the p53 tumor suppressor gene.
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PMID:12-O-tetradecanoylphorbol-13-acetate promotion of transgenic mice expressing epidermal-targeted v-fos induces rasHA-activated papillomas and carcinomas without p53 mutation: association of v-fos expression with promotion and tumor autonomy. 754 54

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.
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PMID:Effects of genetic background on tumorigenesis in p53-deficient mice. 754 19

To identify common regions of deletion in human testicular germ cell tumors (TGCTs), we have screened tumors from 33 patients for loss of heterozygosity (LOH) using Southern blot analysis with 39 polymorphic markers covering 21 chromosome arms. Losses in more than 2 tumors and occurring at a frequency of > 10% were found on chromosome arms 5q, 11p, 11q, 13q, and 16p, the highest being on chromosome arm 5q (19%). It is suggested that tumor suppressor genes on 5q among others may be involved in testicular tumorigenesis and that LOH in this region requires further investigation. No losses were found on 12q and 17p despite the fact that the most common cytogenetic abnormality in TGCTs is an i(12p) and that the TP53 gene on 17p is the most frequently mutated gene in human cancers. The level of allelic imbalance varied considerably from one chromosome region to another (0-80%) and did not generally reflect the pattern of LOH. It tended to be high in overrepresented regions of the genome, 1q, 7p, and 12p. The tumor from one patient had a seminomatous component and a less differentiated component. We provide evidence for a common origin of both components and show that it is likely that this tumor has progressed from the seminoma to the less differentiated histology.
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PMID:Loss of heterozygosity on chromosome arms 5q, 11p, 11q, 13q, and 16p in human testicular germ cell tumors. 754 32

Overexpression of the p53 tumour suppressor gene is one of the most common abnormalities in primary human cancers and appears to be a result of point mutation within a highly conserved region of the gene with subsequent encoding for a mutant, more stable protein. In the study, 71 surgically resected hepatocellular carcinomas (HCC) were examined to study the expression of the p53 gene, its relation with clinicopathological parameters and its prognostic significance. Using immunohistochemical detection for mutant p53 protein with monoclonal antibody PAb1801, p53 overexpression was found in 22 tumours (31%) but in none of the non-tumorous liver specimens. Overexpression of p53 was more frequent in tumours with poor cellular differentiation (P = 0.01), in tumours > 5 cm in diameter (P = 0.05), and in those with giant cells present (P = 0.03) and, less significantly, of massive type of Eggel's classification (P = 0.06). It did not have any significant correlation with hepatitis B or C status, background liver disease or serum alpha-fetoprotein levels, nor was it related to tumour invasiveness (venous permeation, direct liver invasion and tumour microsatellite formation). In addition, the presence of p53 mutant protein did not influence tumour recurrence or patients' survival rates. The data suggested that p53 mutation in HCC was associated with a later stage of oncogenesis. However, it was not apparently related to tumour invasiveness/aggressiveness and prognosis.
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PMID:Overexpression of p53 in hepatocellular carcinomas: a clinicopathological and prognostic correlation. 754 99

A stochastic process model for one-, two-, and three-stage malignant transformation has been developed for embryonic and adult mice. The model has been used to study the influence of mutation rate, number of stages required for transformation, and number of stem cells at risk on the kinetics of spontaneous appearance of malignant tumors. As expected, tumors appeared earlier with fewer required mutational stages, higher mutation rate, and greater number of stem cells at risk. However, a notable observation was that tumor latency was more strongly influenced by number of stages and by stem cell number at lower mutation rates than at higher rates. This implies that tumor latency may be a less useful observation when the spontaneous mutation rate is high. In the future, the model will be applied to analysis of tumorigenesis experiments in transgenic mice with p53 genetic abnormalities, subjected to irradiation or chemical tumorigenesis at different stages of development.
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PMID:A stochastic model for multistage tumorigenesis in developing and adult mice. 754 21


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