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

We have obtained initial evidence supporting a new model for the human disease ataxia-telangiectasia (A-T), in which the A-T and p53 genes play crucial roles in a signal transduction network that activates multiple cellular functions in response to DNA damage. Three of the model's predictions were tested. (1) Disrupting cell cycle checkpoints should increase spontaneous rates in normal cells. In order to interfere with the G1/S checkpoint, we transfected a normal cell line with vectors expressing either a dominant-negative p53ala143 mutant or a human papilloma virus E6 gene. These transformants showed 10-80-fold elevations in spontaneous recombination rates when compared with their parent. (2) A-T cells should be sensitive to DNA damage-induced apoptosis. Widespread apoptosis was detectable in four A-T fibroblast lines, but not two control lines, beginning 24 h after exposure to X-rays or streptonigrin, but not UV. Streptonigrin also induced widespread apoptosis in A-T lymphoblasts but not in control lymphoblasts. (3) Disruption of p53 function in A-T cells should increase their mutagen resistance by interfering with apoptosis. Stable transfection of either the p53143ala or the HPV18 E6 construct was associated with acquisition of streptonigrin and radiation resistance, while transfection with the p53143ala construct did not affect the streptonigrin sensitivity of a control cell line.
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PMID:Testing the role of p53 in the expression of genetic instability and apoptosis in ataxia-telangiectasia. 783 42

A replication-defective recombinant retrovirus containing the human papilloma virus E6/E7 genes (LXSN-16 E6E7) was used to immortalize stromal cells from human marrow. The E6/E7 gene products interfere with the function of tumor-suppressor proteins p53 and Rb, respectively, thereby preventing cell cycle arrest without causing significant transformation. Twenty-seven immortalized clones designated HS-1 to HS-27 were isolated, four of which are characterized in this report. Two cell lines, HS-5 and HS-21, appear to be fibroblastoid and secrete significant levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), macrophage-CSF (M-CSF), Kit ligand (KL), macrophage-inhibitory protein-1 alpha, interleukin-6 (IL-6), IL-8, and IL-11. However, only HS-5 supports proliferation of hematopoietic progenitor cells when cocultured in serum-deprived media with no exogenous factors. Conditioned media (CM) from HS-5 promotes growth of myeloid colonies to significantly greater extent than a cocktail of recombinant factors containing 10 ng/mL of IL-1, IL-3, IL-6, G-CSF, GM-CSF, and KL and 3 U of erythropoietin (Epo). Two additional clones, HS-23 and HS-27, resemble "blanket" cells, with an epithelioid morphology, and are much larger, broader, and flatter when compared with HS-5 and HS-21. These lines secrete low levels of growth factors and do not support proliferation of isolated progenitor cells in cocultures. CM from HS-23 and HS-27 also fail to support growth of myeloid colonies. Both HS-23 and HS-27 express relatively high levels of VCAM-1, yet HS-27 is the only line that supports the formation of "cobblestone" areas by isolated CD34+38lo cells. We hypothesize that HS-5, HS-21, HS-23, and HS-27 represent functionally distinct components of the marrow microenvironment.
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PMID:Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. 784 21

Parameters of genome instability and morphological alterations associated with cell transformation were studied in an isogeneic set of clonal human uroepithelial cell (HUC) lines immortalized by the human papilloma virus 16 (HPV16) E6 and/or E7 gene(s). HPV16 E6 binds p53, leading to rapid degradation of p53, whereas E7 binds and alters pRb and other proteins. We report that two independent E7-immortalized HUC lines showed minimal phenotypic or genotypic alterations, except that both lines contained amplification of 20q DNA sequences and a greater polyploidization at an early passage. The E7-immortalized HUC line resembled normal HUC lines, except that they failed to senesce. In contrast, the E6-immortalized HUC lines were morphologically altered, contained numerous random chromosome aberrations, and showed unstable evolving karyotypes with passage in culture. No amplified DNA sequences were detected in E6-immortalized HUC lines. Instead, clonal losses of chromosome regions (i.e., -3p, -6q, -9p), putatively containing tumor suppressor or senescence genes, accompanied the E6-HUC immortalization event. E6-immortalized HUC lines showed transformed phenotypes similar to E6/E7-HUC lines. The difference in genome stability between E6- and E7-immortalized HUC was highly significant statistically (p-value < 10(-6). Thus, the HPV16 E7 gene led to HUC immortalization by a pathway that blocked cellular senescence, but did not disrupt genome stability. These results implicate p53 loss, but not pRb alteration, in genome destabilization.
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PMID:Long-term genome stability and minimal genotypic and phenotypic alterations in HPV16 E7-, but not E6-, immortalized human uroepithelial cells. 795 91

The 3Y1 cell line, established from a rat whole embryo, is widely used as a normal immortalized fibroblast. We analyzed p53 mutations in four clonal lines derived from the 3Y1 cell line; 3Y1-B clone 1-6, 3Y1-C and two clonal lines (3Y1 cl-3 and 3Y1 cl-6) which had been transformed by the human papilloma virus E6 gene. Polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis and DNA sequencing showed that three clonal lines had a double mutation at codons 130 and 136 on the same allele and that the other clonal line, 3Y1 cl-3, had no mutations. 3Y1-B clone 1-6, which has been registered as the standard clonal line at the Japanese Cancer Research Resources Bank, demonstrated weak bands of the wild type allele, suggesting the existence of heterogeneous cell types in this "clonal" line. PCR-SSCP analysis of 25 subclones obtained by limiting dilution of 3Y1-B clone 1-6 cells revealed a mixture of two types of cells; 12 subclones showed only the bands of mutated allele, and 13 subclones showed both bands of the wild and mutated p53 alleles. These findings should be taken into consideration when using this cell line as a normal immortalized cell line.
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PMID:Presence of p53 mutations in 3Y1-B clone 1-6: a rat cell line widely used as a normal immortalized fibroblast. 801 1

To identify the genetic events which may play a role in the development of cervical carcinoma, we performed a detailed allelotype analysis utilizing DNA from 53 primary tumors and corresponding normal cells and 57 polymorphic probes mapped to each of the chromosomal arms, excluding the short arms of the acrocentric chromosomes. Loss of heterozygosity (LOH) of > 25% was observed at sites on 11 chromosomal arms, which included 1q (26%), 3p (35%), 3q (31%), 4q (46%), 5p (53%), 5q (38%), 6p (28%), 10q (28%), 11p (42%), 18p (38%), and Xq (26%). The most frequent LOH was noted on 4q (ADH3) and 5p (D5S19), suggesting that loss of candidate tumor suppressor genes on these chromosomal arms may play a role in the development of cervical carcinoma. The two sites of deletions identified on 5p and Xq represent novel candidate tumor suppressor gene sites which have so far not been reported in any other tumor type. Human papilloma virus status did not correlate with any of the sites which showed frequent LOH. TP53 mutation analysis by single-strand conformation polymorphism analysis was performed in 17 tumors that either showed 17p deletions (TP53, D17S5, or D17S28) or were human papilloma virus negative. One of the 7 human papilloma virus-negative tumors, which also showed LOH at the D17S28 locus, had a mutation in exon 5. This study represents the first comprehensive genetic analysis of this cancer and identifies several novel features of significance to genetic etiology of cervical carcinoma.
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PMID:Allelotype analysis of cervical carcinoma. 804 99

The inactivation of the tumor suppressor gene p53 has been demonstrated in a variety of human tumors. Herein, we performed a p53 gene analysis of human gynecologic tumor cell lines and tumor tissues. In the SK-OV-3 cell line, Southern analysis suggested the presence of sequence deletions/rearrangements in at least one allele of p53 gene. Transcripts were not detectable by either Northern or PCR analysis. Sequencing analysis of the entire coding region revealed mutations changing the p53 amino acid composition in all six endometrial carcinoma cell lines tested (Ishikawa, Hec1-A, Hec1-B, KLE, RL95-2, and AN-3), and four cell lines in ovarian carcinoma cell lines (Caov-3, -4, OVCAR-3, and Kuramochi). Of the seven cervical carcinoma cell lines, two (HT-3 and C-33A) contained p53 codon changes. We were unable to detect the human papilloma virus (HPV) in these two cell lines. By contrast, five HPV-positive cervical carcinoma cell lines (HeLa S-3, Caski, SiHa, C-41, and ME-180) contained wild-type p53 gene sequences. Examination of loss of heterozygosity (LOH) by PCR revealed that about 30% of the human ovarian carcinoma tissues has LOH at the locus of p53 gene. We suggest that, in the HPV-positive cervical tumors, p53 inactivation occurred via the known mechanism of viral E6/cellular p53 protein association, whereas in all other tumors (ovarian carcinoma, endometrial carcinoma, HPV-negative cervical carcinoma) p53 function was compromised by changes in the amino acid sequence.
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PMID:[Analysis of p53 gene in gynecologic tumors]. 815 58

Specific human papilloma virus (HPV) types appear to be necessary etiological factors for most cervical cancers, yet additional genetic alterations seem to be required for their development and progression. The aim of this study is to determine the likely chromosomes location of tumorigenicity suppressor-like genes, the loss of function of which might be important in the origin or progression of cervical carcinomas. PCR with primers for 75 highly polymorphic microsatellite loci located on the major autosome arms were used to estimate the incidence of loss of heterozygosity (LOH) in 38 tumors. The HPV status of the tumors was also determined. LOH was found to involve 19 chromosome arms in 20-43% of the tumors. Chromosome arms 6p, 3p, and 18q are most frequently involved in LOH in 43, 39, and 35% of the informative carcinomas, respectively. The respective regions involved are 6p21.1-23, 3p13-25.3, and 18q12.2-21.2. LOH is generally limited to specific band segments within these regions. Similar high incidences of LOH of the same 3p segments have been reported in cervical carcinomas from different parts of the world. The same 3p and 6p segments are involved in many types of common cancers, whereas 18q changes are less frequent in other cancers. Chromosome arms 1q, 2q, 3q, 4p, 4q, 5p, 5q, 6q, 7q, 8p, 8q, 11q, 13q, 16p, 18p, and 19p are involved in LOH in 20-33% of the cervical tumors. Chromosome 11 alterations are among the most frequently found in many different types of neoplasias. In this study, 11p was involved in 16% of the tumors, and 11q was involved in 22%. Chromosome 17 alterations are found in more cancers than those of any other chromosome, frequently involving the p53 gene on 17p. LOH of 17p was found in 5 (15%) cervical tumors; 2 of these were HPV negative and expressed mutant p53. In such HPV-negative tumors, direct mutation of the wild-type p53 appears to replace the inactivation of the p53 product by oncogenic HPV types. Tumors with LOH at many loci were, on the average, at more advanced stages, as were tumors with mutant p53. The higher overall incidence of LOH in cervical carcinomas as compared to other cancers, and the diversity of LOH patterns found, suggest that different cervical carcinomas probably arise and/or progress, in part, because of the loss of function of different yet finite sets of tumorigenicity suppressor genes and genes that are involved in tumor progression and metastasis. The findings also indicate that certain chromosome segments that are often altered in cervical carcinomas are also frequently altered in several other types of cancers. It remains to be determined whether the same or different genes located within these segments are involved in the different cancer types.
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PMID:Genomic alterations in cervical carcinoma: losses of chromosome heterozygosity and human papilloma virus tumor status. 854 63

A flow cytometric technique utilizing the continuous incorporation of bromodeoxyuridine (BrdU) into asynchronous cells to measure radiation-induced cell cycle delay is described. Following the incorporation of the BrdU label the cells are stained with ethidium bromide and the bis-benzimidazole Hoechst 33258. These fluorochromes have differential staining patterns. Hoechst 33258 fluoresces blue and is quenched by BrdU incorporated into cellular DNA during S phase. Ethidium bromide fluoresces red and is not quenched by BrdU. Therefore in cells that are cycling and synthesizing DNA new G1 and G2 compartments are created and this can be used to measure cell cycle delays following ionizing radiation to asynchronous cells. We have used this technique to evaluate two cell lines: a normal diploid human embryo fibroblast cell line MRC 5, which has inducible p53 and shows delays at both G1 and G2 checkpoints, and the human cervix carcinoma cell line HX 156. This cell line has been infected with human papilloma virus (HPV) 16, and therefore has inactivated p53 function and is blocked only at the G2 checkpoint. Using this method, cell cycle-dependent effects relating to the G2 block can be observed. The radiation-induced G2 block differs from that induced by drugs or heating in that cells are blocked in G2 irrespective of the phase of the cell cycle they are treated in. This method allows these different types of G2 block to be quantified.
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PMID:Application of a bromodeoxyuridine-Hoechst/ethidium bromide technique for the analysis of radiation-induced cell cycle delays in asynchronous cell populations. 860 62

Primary prostate epithelial and prostate adenocarcinoma cells cultured in serum-free medium grew for up to 10 passages before senescence. Cells from prostate adenocarcinoma of a 55-year-old patient without lymph node involvement were transfected with plasmids containing recombinant human papilloma virus HPV16 or HPV18 DNA and the selectable neomycin-resistance gene. After G-418 selection, cells underwent crisis, and surviving cells infected with retroviruses encoding the HPV18 E6/E7 genes (HPV-PAC1), transfected with a head-to-tail dimer of the complete HPV16 genome (HPV-PAC2), or transfected with HPV18 E6/E7 early genes (HPV-PAC3) were established. HPV-PAC1 and HPV-PAC2 cultures appeared morphologically similar to primary cultures even after 40 passages. However, HPV-PAC2 cultures had a clonal morphology. All lines were positive for cytokeratin 18, had acquired vimentin expression, and contained either HPV16 or HPV18 sequences integrated into host DNA. None was tumorigenic in nude mice or formed colonies in soft agar. These cells did not secrete prostate specific antigen nor respond to androgen although tamoxifen inhibited the growth of the cells. Immunohistochemistry showed no evidence of p53 overexpression. Further characterization of these cell lines and examination of their response to chemotherapeutic agents may provide relevant information for the study of hormone-independent PC.
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PMID:Immortalization of human adult prostatic adenocarcinoma cells by human papilloma virus HPV16 and -18 DNA. 862 Apr 53

To investigate the effects of human wild-type p53 expression on the proliferation of cervical carcinoma cells, a plasmid, pMO7-hp53, which contains a full-length cDNA of the human wild-type p53 (wt-p53) gene, was transfected into a cell line (TMCC-1) derived from an endocervical type, human papilloma virus-positive adenocarcinoma of the uterine cervix. The exogenous wt-p53 expression induced growth suppression, morphological changes, and loss of anchorage-independent growth of the tumor cells. As the wt-p53 gene apparently plays a negative role in growth regulation of cervical carcinoma cells, this gene may possibly be of some use for treating subjects with a cervical carcinoma.
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PMID:Growth suppression of a cervical cancer cell line (TMCC-1) by the human wild-type p53 gene. 863 46


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