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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidence indicates that lung cancer arises due to multiple genetic changes in both dominant oncogenes, such as ras, and tumor suppressor genes, such as p53. In this report we examined whether the wild-type p53 gene is able to suppress in vitro and/or in vivo cellular growth of lung cancer cell lines which carry multiple genetic abnormalities. Introduction of a wild-type p53 complementary DNA expression vector into lung cancer cell lines carrying either a homozygous deletion (NCI-H358) or a missense mutation (NCI-H23) in the p53 gene greatly suppressed tumor cell growth. In contrast, p53 expression vectors bearing lung cancer derived mutations affecting single amino acids had lost this growth suppressing ability.
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PMID:Wild-type but not mutant p53 suppresses the growth of human lung cancer cells bearing multiple genetic lesions. 155 36

Forty-two endometrial carcinomas of various stages of progression were analyzed to search for loss of chromosomal regions and for point mutations of ras genes and amplification of Int-2 gene. This approach is particularly favorable for observation of genetic events and their significance in the process of neoplastic conversion by considering the clinico-pathological characteristics of each tumor. At least 3 genetic events, including 18q, 17p deletions, and point mutations at codon 12 of the K-ras gene, are implicated in the development of endometrial carcinomas. Likely targets for allelic losses on chromosomes 18q and 17p are the DCC gene and the p53 gene sequences, respectively. Overall numbers of allelic losses in individual tumors appeared to increase in case of advanced stage tumors, thereby indicating the association of allelic loss accumulation with tumor progression. The genetic features seen in 2 juvenile-type adenocarcinomas and 2 clear-cell carcinomas suggested the possibility that etiological factors providing selective pressure for particular mutation sub-sets during carcinogenesis are probably heterogeneous.
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PMID:Chromosomal deletions and K-ras gene mutations in human endometrial carcinomas. 156 44

The ras, Rb and p53 genes have been implicated in the development of human breast cancer. Qualitative or quantitative changes in the expression of the ras p21 may lead to cell transformation, and this has been previously demonstrated in breast cancer. Both the retinoblastoma protein (Rb1) and the p53 gene product appear to function as negative regulators of cell division. We have investigated the expression of ras p21, Rb1 and p53 proteins in human breast cancer patients immunohistochemically, and correlated the results with a range of clinical and pathological parameters. Ras p21 expression was elevated in 65 per cent and p53 in 23 per cent of cases. Rb1 was expressed in 58 per cent of breast cancer tissues and in 75 per cent of normal tissue. Only four patients were found to have loss of Rb1 expression and also overexpression of both p53 and ras gene products. No correlations were found between the expression of these three genes and menopausal status, histological types or tumour grade. However, a correlation was found between Rb1 loss of expression and tumour diameter (greater than 2 cms), and no lymph node metastasis. Also, a significantly higher number of p53 staining specimens were found to be overexpressing the ras gene. These results suggest that all three oncogenes are most likely involved in the development of breast cancer but that their role is complex.
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PMID:Expression of ras Rb1 and p53 proteins in human breast cancer. 156 85

Mutant p53 and activated ras cDNA clones cooperate to fully transform primary rat embryo fibroblasts in cell culture, whereas neither cDNA alone results in the full transformation of these cells. The mutant p53 protein may be required to initiate the transformation event with ras. Alternatively, mutant p53 gene expression may be required to maintain the properties of the transformed phenotype. To distinguish between these possibilities, primary rat embryo fibroblasts were transformed with mutant p53 plus ras cDNAs, where the expression of the p53 gene was regulated by an isopropyl beta-D-thiogalactoside-responsive promoter. When expression of the mutant p53 cDNA was inhibited and no detectable exogenous p53 protein was produced, both the growth rate and the morphology of the cells reverted to a normal phenotype. These results demonstrate that a mutant p53 protein is required for the maintenance of the transformed phenotype in cells transformed with p53 plus ras cDNAs.
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PMID:A mutant p53 protein is required for maintenance of the transformed phenotype in cells transformed with p53 plus ras cDNAs. 157 Mar 19

The last decade has seen major advances in the acquisition of knowledge concerning both the cellular and molecular genetics of multiple myeloma. Although discrete and specific changes associated with the plasma cell disorders have yet to be identified, a pattern is emerging that one can associate with the plasma cell disorders. This pattern includes the frequent involvement of chromosomes 1 and 14, and in particular presence of the 14q+ abnormality. But in addition there are typically many other numeric and/or structural changes that can, in fact, involve almost any chromosome, but particularly chromosomes 3, 5, 6, and 7, as well as 11, 14, 17, and 18. The presence of one or more unidentified marker chromosomes is also a typical feature. The ongoing challenges include identification of a crucial initial genetic change (if such exists) as well as the factors contributing to the ongoing karyotypic evaluation that results in complex karyotypes in patients with advanced disease. There is no doubt that the complex karyotypic picture contributes to the major heterogeneity of plasma cells that occurs in malignant plasma cell disorders. Karyotypic complexity underlies heterogeneity in cell morphology, surface antigen expression, response to cytokines, and a variety of other functional characteristics. The aberrant expression of antigens normally found on other hematopoietic progenitors has led to speculation about the true nature of the stem cell in myeloma. The overriding challenge, however, is to fully understand the plasma cell disorders at the molecular level. Although changes have already been noted in the functions of C-myc, the ras family of oncogenes, Bcl-2 expression, and several so called anti-oncogenes such as p53, it is likely that we have only begun to scratch the surface in the area of molecular changes. The potential for involvement at multiple molecular sites and the possibility of complex interactions between gene segments is truly overwhelming. However, it is hoped that at the molecular level a pattern will ultimately emerge. It is most interesting, as previously discussed, that there is an interplay among C-myc, N-ras, Bcl-2, and the Epstein-Barr virus in the predilection for a plasma cell phenotype. Undoubtedly there is much more to learn, and it is truly exciting to finally have some tools and probes at hand to more effectively study the genome in multiple myeloma and related disorders.
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PMID:Cellular and molecular genetic features of myeloma and related disorders. 158 85

We investigated the mechanism of radiation induction of murine thymic lymphomas by studying the characteristics of primary x-ray-induced thymic lymphoma (PXTL) cell lines and of their oncogene-induced, progressed progeny. It is widely thought that proto-oncogene alterations are associated with the induction of murine lymphomas; however, few, if any primary murine radiation-induced lymphomas possess (proto-)oncogene alterations. Independently derived cell lines grown directly (i.e., without in vivo transplantation) from thymic lymphomas of irradiated C57BL/6 mice possess the properties of immortalized pre-T cells and lack many of the characteristics of "tumor cells". PXTL cells are poorly tumorigenic upon transplantation, do not clone in methylcellulose cultures, are growth factor dependent and autocrine, and lack consistent chromosome and oncogene abnormalities. However, the thymic lymphomas are malignant and cause the death of each afflicted mouse. PXTL cells expressed two immunologically distinct forms of the tumor suppressor protein p53 that have moderately increased stability (t1/2 = 1 h) when compared with p53 of normal splenic T lymphocytes. Early PXTL cells could progress in vitro to a fully tumorigenic phenotype after infection with retroviruses encoding the c-myc and v-ras oncogenes. Progressed T-lymphoma cells acquired growth factor independence, a highly transplantable and tumorigenic phenotype, and the ability to quantitatively clone in methylcellulose cultures. Progressed lymphoma cells coordinately downregulated the expression of five T-cell differentiation markers, upregulated the expression of CD44 (Pgp-1), and harbored vastly elevated levels of two immunologically distinct forms of p53. Our results suggest that the early thymic lymphomas consist of differentiation-inhibited, immortal pre-T cells that are precursors to progressed, fully tumorigenic T-lymphoma cells.
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PMID:Association of induction of a fully tumorigenic phenotype in murine radiation-induced T-lymphoma cells with loss of differentiation antigens, gain of CD44, and alterations in p53 protein levels. 158 48

Mutation of the p53 gene is a key element in the development of several human cancers. Intron 4, a noncoding region of the p53 gene, is required for optimal expression of that gene. We have previously shown that nuclear protein binds intron 4 and have defined the protein-binding site. In this paper we address the question, "Does the mutant p53 gene's ability to transform cells to the malignant phenotype depend on protein binding to intron 4?" Using an in vitro assay in which the mutant p53 gene and Ha-ras oncogene cooperate in transformation of cells to the malignant phenotype, we determined the ability of mutant mouse p53 gene constructs, with and without two base pair substitutions at the intron 4 protein-binding site, to participate in malignant transformation. On Day 1, 5 x 10(5) rat embryo fibroblasts were transfected by the calcium phosphate procedure with 10 micrograms of both a mutant p53 gene construct and Ha-ras oncogene. Malignant transformation was evidenced by the formation of discrete foci of heaped-up cells. After 14 days of incubation at 37 degrees C in DMEM and 10% fetal calf serum (8% CO2), the cells were stained with cresyl violet and the foci counted. In three separate experiments, the presence of two base pair substitutions at the intron 4 protein-binding site caused a significant decrease in the number of foci formed (P less than 0.05).
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PMID:Inhibition of the mutant p53 gene in transformation assays. 159 78

The tumor suppressor gene p53 has been shown to be mutated in 50% of acute lymphoblastic T-cell-leukemia (T-ALL) cell lines, all of which were established from T-ALL cases in relapse. In these lines both alleles of the p53 gene were independently affected by point mutation. In contrast, in human solid tumors possessing a mutated p53 allele, the second wild-type p53 suppressor allele is often lost by deletion rather than altered by mutation. This suggests that in T-ALL cell lines, the product encoded by the second mutated allele provides the cells with an additional oncogenic stimulus, beyond the loss of suppressive activity. While different p53 mutations have been shown to possess differential oncogenic potential in the p53 plus ras cotransformation assay, in T-ALL cells different mutations may in addition possess distinct functions, further contributing to the tumorigenic phenotype.
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PMID:Role of the p53 tumor suppressor gene in the pathogenesis and in the suppression of acute lymphoblastic T-cell leukemia. 160 34

Genetic analyses of unusual hereditary cancers and of common neoplasms suggest that tumorigenesis proceeds through a series of genetic alterations involving oncogenes and tumor-suppressor genes. Such genes can be viewed as tumor-susceptibility genes, and DNA tests that examine them might be useful in determining an increased risk of cancer development before the onset of a tumor. Indeed, DNA tests have already proved useful in the genetic counseling of families with an increased risk of rare inherited diseases such as retinoblastoma, multiple endocrine neoplasia type 2a, or Li-Fraumeni syndrome. The current investigation of these familial disorders is enabling the development of expertise, reagents, and methods that will eventually focus on the most common cancers. In assessing risk for these common tumors, several genes will probably require study to achieve more accurate prediction of cancer risk. For example, genetic abnormalities of the ras oncogene and of either the retinoblastoma gene (Rb) or the p53 tumor-suppressor gene have been found in many tumors and appear to be particularly important in the study of individuals at increased risk of lung, breast, or colon cancers. In addition, the study of tumor-associated markers that might already be detectable in the preneoplastic state can be carried out in parallel with tests that search for evidence of mutations in tumor-susceptibility genes. Finally, both classes of markers might be complementary in genetic counseling or screening of populations at increased risk. However, the capacity for detecting tumor-susceptibility markers creates a responsibility for the physician in terms of the proper use of this information.
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PMID:Tumor-susceptibility markers. 161 94

Genomic DNA from thymus tissue obtained from 47 C57BL/6J animals treated with the DNA alkylating agent N-methylnitrosourea or gamma-irradiation were screened for the presence of p53 mutations by using the single strand conformation polymorphism assay. Mutations were detected in 13% (4 of 30) of primary thymic lymphomas but none of 17 early stage lymphomas. The frequency of p53 mutations was the same in tumors induced by N-methylnitrosourea (2 of 15) or by gamma-irradiation (2 of 15). Mutations occurred in the highly conserved regions of the p53 gene in exons 5, 7, and 8. G:C to A:T transitions were commonly observed. One of 4 of the tumors analyzed contained two p53 mutations in exons 7 and 8. A previous study of the same tumors showed that ras mutations occurred with high frequency (greater than 50%) (E. W. Newcomb et al., Cancer Res., 48:5514-5521, 1988). Our data suggest that p53 mutations do not play a major role in carcinogen-induced thymic lymphomas studied here.
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PMID:p53 mutations in C57BL/6J murine thymic lymphomas induced by gamma-irradiation and N-methylnitrosourea. 161 48


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