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

Rearrangements within the p53 gene are observed in a high proportion of independent erythroleukemic cell lines derived from the spleens of mice infected with Friend leukemia virus. The majority of cells with at least one rearranged p53 allele do not express detectable levels of p53 protein. Here, we show that in 4 out of 19 newly established erythroleukemic cell lines induced by infecting DBA mice with either the anemia (FV-A) or polycythemia (FV-P)-inducing strains of Friend virus, the p53 gene is rearranged as a result of integration of spleen focus-forming virus (SFFV). Integration of SFFV within the p53 gene resulted in inactivation of gene expression as determined by Western blot analysis. The sites of SFFV integration in the p53 gene were found, by Southern blot analysis and the polymerase chain reaction, to be localized in a 1-kbp region between introns 7 and 9. In addition, loss of the normal p53 allele was observed in three of the erythroleukemic cell lines that carried a rearranged p53 gene. Insertion of SFFV in these cell lines resulted in either the appearance of aberrant p53 transcripts or the complete lack of p53 expression. The results presented in this paper demonstrate that retroviral insertions can not only contribute to neoplastic transformation by activating dominant oncogenes but also by inactivating genes that normally function in a negative way to control cell growth. Thus, it may be possible to identify additional genes of this class by characterizing chromosomal sequences that are adjacent to common sites of retroviral integration in tumors.
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PMID:Insertional inactivation of the p53 gene during friend leukemia: a new strategy for identifying tumor suppressor genes. 210 28

The protein p53 has been reported to be associated with cell transformation and/or proliferation. Using p53 monoclonal antibodies we estimated by flow cytometry the relative content of this protein in individual L1210 leukemic cells from exponentially growing and plateau-phase cultures and compared it with that in normal thymocytes of parental DBA/2 mice and in mitogen-stimulation and nonstimulated human lymphocytes. Simultaneous differential staining of p53 vs DNA and p53 vs RNA, followed by bivariate analysis, made it possible to estimate p53 with respect to cell position in the cell cycle and correlate it with RNA (predominantly rRNA) content. The data show that in exponentially growing L1210 cells p53 is being progressively accumulated during the G1, S and G2 phases and that the content of p53 and RNA are highly correlated. In plateau L1210 cultures most cells are arrested in G1, some cells, however, still continue to progress through S and G2. In these cultures the p53 content of all cells, regardless of the phase of the cell cycle, is diminished and the decrease in p53 is more pronounced than that of RNA or total protein content. The normal thymocytes as well as the stimulated lymphocytes show bimodal distribution with respect to p53 expression, compatible with the assumption that the cycling cells have increased expression of this protein related to the G0 cells. Some cycling cells, however, have minimal p53. The quantitative p53 immunofluorescence data were confirmed by the immunoprecipitation and gel electrophoresis. The results suggest that expression of p53 in leukemic and normal cells is more correlated with cell growth than with entrance to the cell cycle or progression through particular phases of the cycle.
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PMID:p53 content in relation to cell growth and proliferation in murine L1210 leukemia and normal lymphocytes. 243 61

The p53 gene is rearranged in a high proportion of erythroleukemic cell lines derived from the spleens of mice infected with Friend leukemia virus. These rearrangements result in either the synthesis of a truncated protein or the inactivation of the p53 gene. Here we have molecularly characterized the rearrangements in two murine erythroleukemic cell lines induced by Friend leukemia virus, DP20-1 and CB3, that contain a rearranged p53 gene and fail to express p53 protein. The rearrangement in the DP20-1 cell line is due to the insertion of Friend spleen focus-forming provirus (SFFV) in the 3' end of the p53 gene in intron sequences between exons 9 and 10. Transfection of molecular clones of this SFFV provirus into NIH3T3 cells results in the generation of infectious virus as determined by its ability, in the presence of helper virus, to induce rapid splenomegaly and polycythemia when injected into adult DBA/2J mice. Insertion of SFFV in DP20-1 cells resulted in the expression of an aberrant 2.9 kb RNA species. Analysis of a molecular clone of the rearranged p53 gene in a second cell line, CB3, revealed that the p53 gene in this clone has sustained a large deletion within the p53 gene resulting in the loss of coding sequences between exons 4 and 8. The 5' end of the deletion originates within exon 4 and extends 3' to within the eighth intron. The significance of these findings with regard to the multi-stage nature of Friend virus induced erythroleukemia is discussed.
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PMID:Inactivation of the p53 oncogene by internal deletion or retroviral integration in erythroleukemic cell lines induced by Friend leukemia virus. 284 14

The spleens of old NZB mice have an abnormal population of B cells with extra chromosomes. These hyperdiploid B cells manifest increased proliferative capacity; they grow in (NZB X DBA/2)F1 spleens after intravenous injections. Molecular analysis of individual old NZB and F1 passaged spleens demonstrate that hyperdiploid cells represent a clonal or oligoclonal expansion of B cells. All spleens with at least 10% hyperdiploid cells demonstrated both heavy and kappa light chain immunoglobulin gene rearrangements by Southern blot hybridization. None of the hyperdiploid spleens from old NZB mice had lambda rearrangements and only one of five showed evidence of clonal rearrangement of the TCR-beta gene. One also had a VK10 clonal rearrangement. Elevated p53 oncogene protein was observed in NZB hyperdiploid spleen cells; however, no p53 or other oncogene rearrangements or amplifications were seen. Hyperdiploid cells were IgM-bright, IgD-dull, Ia+, dull B220, Thy-1-, and Ly-1-dull. Spleens with hyperdiploid B cells had increased percentages of Ly-1 B cells. The data suggest that hyperdiploid cells in old NZB mice represent clonal expansion of B cells and that they may represent an intermediate stage between autoimmunity and malignancy.
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PMID:Clonal expansion of abnormal B cells in old NZB mice. 311 60

2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), a food mutagen, induces forestomach tumors in CDF1 mice. We established a polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis system to detect mutations in the mouse p53 gene exons 2-10, which encompass all five regions conserved among species, and a system to examine loss of heterozygosity (LOH) that uses newly identified polymorphisms between BALB/c and DBA mice, the parental strains of CDF1 mice. Four original forestomach tumors (one papilloma, two carcinomas, and one lymph-node metastasis) and four cell lines derived from four independent forestomach tumors were examined with the PCR-SSCP system and by polymorphism analysis. Of the four original tumors, the papilloma had a G-->A transition at the second position of codon 171, and one carcinoma had a G-->T transversion at the second position of codon 113 with loss of the wild-type allele, whereas the other two carcinomas had no detectable mutations. Of the four cell lines, two had a base substitution and LOH, and the other two had double mutations (a base substitution and a deletion). By amplification of the double mutations in a fragment, the two cell lines were shown to have four kinds of alleles, indicating induction of recombination within the p53 gene. Our results show that our PCR-SSCP analysis system is efficient for detecting p53 mutations in mouse genomic DNA and that alteration of the p53 gene plays a significant role in MeIQ-induced mouse forestomach carcinogenesis.
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PMID:Mutation, loss of heterozygosity, and recombination of the p53 gene in mouse forestomach tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline. 781 62

Strain variation in the mouse p53 gene sequences was investigated in various regions of the gene in 14 inbred strains of laboratory mice and one Japanese wild mouse strain (Mus musculus molossinus Mishima, M. MOL-MSM). Nucleotides within p53 introns 1 and 7, found to be identical in 10 of the laboratory strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, CBA/J, CE/J, NZB, and SWR/J), were substituted for other nucleotide sequences in common with M. MOL-MSM and the four other strains (DBA/1J, DBA/2J, I/LnJ, and P/J). The latter were documented to have originated from a common ancestor. These observations thus suggested the possibility that the p53 gene may have become substituted by outcrossing of this ancestral strain with Asian mice; this is presumably related to the documentation that Japanese mice brought to western countries were used as laboratory mice early in this century. To establish p53 gene heterozygosity, female C3H/HeJ and male DBA/2J mice were mated to produce F1 hybrids (C3D2F1). Electrophoresis of PCR fragments including polymorphic regions with or without restriction enzyme digestion, allowed clear distinction of paternal and maternal p53 alleles. These markers, therefore, should be useful for studying the loss of heterozygosity of the p53 gene during the carcinogenic process.
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PMID:Homology of p53 intronic sequences between four laboratory mouse strains and Japanese wild mouse (Mus musculus molossinus Mishima). 782 35

Some of the progeny of isolated mouse embryo fibroblasts acquire the ability to grow indefinitely during cultivation, presumably through some mutational events. The relevance of p53 mutations and loss of heterozygosity to the mechanism of such immortal growth capability remains controversial. Since four bases in intron 1 of the p53 gene in C3H/HeJ mice are replaced by 13 different bases in DBA/2J mice, it is possible to distinguish maternal and paternal p53 alleles in the cells of F1 hybrids of these strains (C3D2F1) by electrophoresis of polymerase chain reaction fragments including the region. We established 23 spontaneously immortalized fibroblast cell lines from C3D2F1 mouse embryos and 29 transformed cell lines induced from one of the immortal cell lines, either by treatment with chemical carcinogens or by transfection with the c-Ha-ras gene. Of these 52 cell lines, only one, derived from fibroblasts unpassaged for 4 mo, showed p53 gene loss of heterozygosity and a structural alteration in the remaining allele. Our results demonstrated that p53 mutations are not a strict requirement for immortalization and transformation of mouse embryo fibroblasts in vitro.
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PMID:Infrequent loss of heterozygosity and mutation of the p53 gene in immortal and transformed mouse embryo fibroblasts. 818 30

Three h after whole-body irradiation (8 Gy) of C57BL x DBA/2 F1 mice, p53 protein was expressed strongly in the stem cell compartment of the small intestine but at lower levels in the colon. At this time, apoptotic cells were also observed in the stem cell position of the small intestine, with fewer in the colon. In mice without copies of the p53 gene (nulls), the levels of spontaneous apoptosis, in both the small intestine and the colon, were not different from wild-type. Irradiation of the nulls with 8 Gy of gamma-rays failed to induce any further apoptosis: the loss of p53 essentially rendered the epithelial cells, from both the small intestine and the colon, radioresistant. The response of the epithelial stem cells of the small intestine suggests that p53 may play a role in the deletion of damaged cells with carcinogenic potential, whereas this process is limited in the colon.
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PMID:The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. 830 19

An allelotype analysis of lung tumors in mouse hybrids was conducted to identify common regions of allelic loss. By using 50 informative genetic markers, the autosomes of 36 (A/J x C3H/HeJ) F1 adenocarcinomas were examined. Additional adenocarcinomas from as many as 72 (C3H/HeJ x A/J) F1 and 15 (BALB/cJ x DBA/2J) F1 hybrids also were analyzed for DNA loss at some of the loci. Loss of heterozygosity (LOH) was observed at multiple loci and occurred with the most regularity at markers on chromosomes 12 (28%), 14 (28%), 11 (21%), and 1 (20%). The frequency of LOH was not greater than 11% on any of the other chromosomes. Chromosomes 11 and 14 often displayed allelic loss at markers located near the p53 and retinoblastoma tumor suppressor loci, respectively. LOH at markers on chromosomes 12 and 14 was associated with tumors having overall frequencies of allelic loss that exceeded the median value. Losses on chromosomes 1, 11, 12, and 14 also showed a significant association with the adenocarcinoma stage of mouse lung tumorigenesis, suggesting that the inactivation of tumor suppressor loci on these chromosomes may participate in the progression of these tumors.
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PMID:Loss of heterozygosity on chromosomes 1, 11, 12, and 14 in hybrid mouse lung adenocarcinomas. 864 30

The occurrence of different components of the cell growth regulation pathway as expressed in experimental skin carcinogenesis in haired carcinogen-sensitive NMRI, in haired carcinogen resistant DBA/2 mice and in hairless SKH/1 mice was studied by morphological and immunohistochemical methods. The results were compared with respect to neoplastic response, number of tumors, tumor behaviour and to the inducing agent (UV irradiation or chemical carcinogen), in order to increase our understanding of specific alterations in neoplastic development caused by extraneous agents and to determine their possible usefulness as indicators of carcinogen exposure. The expression of growth factors (transforming growth factor alpha and epidermal growth factor), growth factor receptors (epidermal growth factor receptor/c-erbB-1 and c-erbB-2/neu), cell signalling component c-myc, the nuclear transcription factor Harvey-Ras and the tumor suppressor gene p53, were studied in carcinogen- and UV-induced tumor formation in mouse. The results showed increased oncogene expression as well as growth factor expression in the skin during tumor development appearing early in neoplastic and premalignant conditions and becoming more distinct during neoplastic progression. Efforts to delineate specifically initiated cells prior to the appearance of morphologically detectable alterations including dysplasia, papilloma formation and squamous cell carcinomas, were unsuccessful. Increased staining by antibodies to growth factors and oncogenes were also observed in DBA/2 animals resistant to tumor formation. It is concluded that oncogene expression and growth factor protein deposits are associated with carcinogenic effects, partly explaining the mechanism of action of these agents, but the applicability, as such, for the analysis of potential hazardous agents needs further studies.
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PMID:Oncogenes and growth factors as indicators of carcinogen exposure. 867 68


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