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

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

Malignant transformation of primary cells requires at least two distinct and characteristic alterations in cellular behaviour. The first, cellular immortality, can be induced by chemical carcinogens or by cloned oncogenes such as polyoma large T (ref. 4), adenovirus early region 1A (E1A) or the oncogene from avian (MC29) myelocytomatosis virus, v-myc. Cells whose in vitro life-span has been extended by these procedures can be fully transformed by transfection with oncogenes belonging to a different complementation group, including genes of the ras family, adenovirus E1b and polyoma virus middle T (refs 4, 5). The unstable cellular phosphoprotein p53 is frequently present at elevated levels in transformed cells and is stabilized by the formation of complexes with simian virus 40 (SV40) large T or adenovirus E1b 57K protein. Although several reports have associated p53 with cell proliferation, its role remains obscure. We have cloned complementary DNA sequences encoding murine p53 and report here that transfection of p53 expression constructs into cells of finite lifespan in vitro results in cellular immortality and susceptibility to transformation by a ras oncogene.
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PMID:Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53. 609 17

Mutations in the tumour-suppressor gene p53 are the most frequent molecular alterations detected in human tumours. p53 protein, which has been called "guardian of the genome", seems to play a key role in cellular DNA repair. Loss of p53 protein function by genetic mutation thereby makes the cell vulnerable to DNA damage, and disposes it to malignant transformation. In different human tumour types the prognostic relevance of p53 alterations is quite variable: While there is evidence of poor prognosis in breast cancer carrying p53 alterations, no such prognostic correlation could be found in low grade astrocytic gliomas. In both tumour types p53 mutations are equally frequent. Malignant transformation is considered a multistep process, and p53 mutations occur at different positions in this cascade in different tumour types. While p53 mutations seem to be an early event in astrocytic gliomas, they affect e.g. colon tumours rather late, during malignant progression from adenoma to carcinoma. These observations underscore the biological importance of p53 mutations in human tumour formation, even if the simple investigation for a prognostic relevance may lead to different results in tumours of different tissues.
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PMID:[p53: an important or most overvalued tumor gene?]. 784 Aug 29

More than 90% of epithelial ovarian cancers arise from single cells. Malignant transformation can be associated with a number of molecular alterations including upregulation of tyrosine kinases and phosphatases, physiologic activation o ras, mutation of p53, amplification of myc, and increased activity of matrix metalloproteinases 2 and 9. Proliferation of transformed epithelial cells can be enhanced through the persistence of autocrine growth stimulation by TGF-alpha, loss of autocrine growth inhibition by TGF-beta, as well as paracrine growth stimulation by macrophage derived cytokines and OCAF, a novel lyso-phospholipid. Ascites tumor cells retain responsiveness to growth inhibition by TGF-beta which induces apoptosis in malignant ovarian epithelial cells, but not in normal ovarian surface epithelium. Proliferation of surface epithelial cells following ovulation may contribute to the pathogenesis of ovarian cancer. Use of oral contraceptives that suppress ovulation has been associated with reduced risk of ovarian cancer in later life. Retinoids also deserve further evaluation for chemoprevention. Treatment with fenretinide was associated with decreased incidence of ovarian cancer. Additive or synergistic inhibition of ovarian tumor cell proliferation has been observed with TGF-beta in combination with all-trans-retinoic acid. Early detection of ovarian cancer could improve survival. Transvaginal sonography (TVS) and serum markers such as CA-125 have been evaluated in multiple clinical trials. The former lacks adequate specificity, whereas the latter is not sufficiently sensitive. Use of multiple serum markers can improve sensitivity. A combination of CA-125, M-CSF and OVX-1 has detected > 95% of Stage I ovarian cancers. If similar results are obtained with different data sets, multiple serum markers could be used to trigger the performance of TVS, providing a potentially cost effective screening strategy. Prospective trials will be required to demonstrate that screening for early stage ovarian actually impacts on survival.
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PMID:Molecular approaches to prevention and detection of epithelial ovarian cancer. 874 99

Malignant transformation and tumor progression are currently thought to be the result of the accumulation of genetic alterations in critical genes, the proto-oncogenes and the tumor suppressor genes. Among the tumor suppressor genes, the p53 tumor suppressor gene mutations are the most prevalent. In order to determine genetic instability and p53 expression, we analyzed the genetic changes of chromosome 9 and 17 by non-isotopic in situ hybridization in formalin-fixed, paraffin embedded tissues and calculated for normalized chromosome index (NCI) and polysomy index (PI), and the expression of p53 by using immunohistochemistry (IHC). The means of chromosome 9 and 17 NCI were found to increase gradually as the tissues progressed from normal to squamous cell carcinoma; 1.02 and 1.03, respectively, in normal adjacent tissue (ANL), 1.19 and 1.20 in hyperplasia (HYP), 1.28 and 1.31 in mild dysplasia (MD), 1.38 and 1.43 in moderate dysplasia (ModD), 1.39 and 1.66 in severe dysplasia/carcinoma in situ (SD/CIS), and 1.65 and 1.83 in squamous cell carcinoma (SCC). Moreover, the PI 9 and 17 means also increased as the tissues passed from histologically normal epithelium to HYP to dysplasia (DYP) to cancer. In ANL, PI 9 and 17 means were 0.90 and 1.53 percent, compared to 3.78 and 3.38 percent in HYP, 3.73 and 5.12 percent in MD, 5.66 and 8.47 percent in ModD, 13.56 and 20.99 percent in SD/CIS, and 17.74 and 22.50 percent in SCC. Interestingly, p53 expression also increased continuously, not only in amount but also in the incidence of its expression, as the tissues progressed from normal to cancer, 2.29 percent in ANL, 4.65 percent in HYP, 9.09 per cent in MD, 9.58 per cent in ModD, 29 percent in SD/CIS, and 38.67 per cent in SCC in the amount; and 3 of 33 (9%) in ANL, 6 of 37 (16%) in HYP, 5 of 21 (24%) in MD, 3 of 12 (25%) in ModD, 8 of 18 (44%) in SD/CIS, and 24 of 49 (49%) in SCC in the incidence. Our studies demonstrated that genetic instability and p35 expression occurred very early from ANL to SCC and increased gradually through HYP, DYP, to SCC in head and neck cancer. The genetic instability and the loss of normal p53 function play the potential role in multistep tumorigenesis in head and neck cancer and might be the useful biomarkers in assessing the risk of tumor development.
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PMID:Genetic instabilities of chromosome 9, 17 and accumulation of p53 overexpression during multistage tumorigesis in head and neck cancer. 907 Oct 74

Human papillomavirus type 16 (HPV-16) is a DNA tumour virus that has been implicated in the development of cervical cancer. In non-transformed HPV-infected cells, the HPV E2 protein regulates transcription of the viral E6 and E7 oncogenes. Malignant transformation is usually accompanied by disruption of the E2 gene and consequent deregulated expression of E6 and E7. Here we show that re-introduction of the HPV-16 E2 protein into an HPV-16-transformed cervical carcinoma cell line results in a decrease in growth rate and, in the absence of serum growth factors, cell death via apoptosis. E2 expression increases E6/E7 mRNA levels. This brings about an increase in E7 protein levels, which in turn leads to an increase in free E2F, a condition that has previously been shown to induce apoptotic cell death. Despite the increase in E6 mRNA there is no detectable E6 protein in these cells and E2 expression does not reduce the activity of a p53-responsive promoter. Our data suggest that disruption of the E2 gene produces HPV-transformed cells that are less liable to undergo apoptosis and, therefore, more likely to form cervical tumours.
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PMID:Disruption of the human papillomavirus type 16 E2 gene protects cervical carcinoma cells from E2F-induced apoptosis. 936 88

The human polyomaviruses JC virus (JCV) and BK virus (BKV) have long been known as onco- and neurooncogenic. Interest in their oncogenic potential has reemerged with the discovery of simian virus 40 DNA in human brain tumors including the pituitary as well as in bone tumors and mesotheliomas. The only human disease caused by an infection with the human polyomavirus JCV is progressive multifocal leukoencephalopathy (PML) characterized by a lytic infection of oligodendrocytes with consecutive demyelination. Malignant transformation of cell lines appears to be caused by a complex interaction of the viral large T (tumor) antigen with several transcription factors and tumor suppressor proteins such as p53 and the retinoblastoma protein. PML, once an extremely rare disease, has become much more frequent in the western world owing to the AIDS pandemic. An exceedingly complicated, cell-, tissue- and species-specific pattern of protein-DNA interaction and negative as well as positive feedback regulation by at least a dozen proteins and possibly mutations in the JC viral promoter-enhancer region govern host range and development of PML. The intricate molecular and immunological prerequisites ultimately leading to PML in humans have not yet been completely elucidated.
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PMID:Progressive multifocal leukoencephalopathy: molecular biology, pathogenesis and clinical impact. 945 Feb 27

Endometriosis is a common gynecological disease in which tissue similar to the endometrium proliferates at sites outside the uterine cavity. Malignant transformation of endometriosis to endometrioid and clear cell ovarian carcinomas has been documented in histological studies, but no molecular genetic evidence exists to support that endometriosis is the clonal precursor of such malignancies. We examined 14 cases of endometriosis synchronous with ovarian cancer for loss of heterozygosity on 12 chromosome arms, X chromosome inactivation, and TP53 mutation to determine whether they shared genetic alterations. In all four of the cases where the carcinoma had arisen within endometriosis and in five of the seven cases where the carcinoma was adjacent to the endometriosis, common genetic lesions were detected, consistent with a common lineage. A TP53 mutation was also detected in one case of endometriosis adjacent to carcinoma. These findings support the numerous histological observations that endometrioid and clear cell ovarian carcinomas may arise through malignant transformation of endometriotic lesions.
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PMID:Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. 956 87

In vitro changes of normal human keratinocytes (NHKs) derived from the oral mucosa after treatment with the chemical carcinogen 7,12 dimethylbenz[a]anthracene (DMBA; 5, 50, 200 ng/10 ml) were evaluated. NHKs were also treated with chemopreventive nutrient agents that previously had enhanced growth of epidermal and oral keratinocytes or suppressed growth of oral squamous cell carcinoma. These agents included the carotenoids beta-carotene and canthaxanthin and the retinoid retinyl palmitate (60 microM). Plating efficiency, growth in agarose (independent growth), viability [tetrazolium salt (MTT) assay], and proliferation ([3H]thymidine labeling) defined the growth of NHKs. The number of cornified cells and keratin expression (high-molecular-weight keratin) defined differentiation. gamma-Glutamyl transpeptidase, p53 expression, and tumorigenesis in mice defined oxidation and malignant transformation. Treatment with DMBA (50 ng/10 ml) was detected by autofluorescence; it produced an increase in pleomorphism and multinucleation and enhanced plating efficiency and the number of colonies grown in agarose. Chemopreventive treatment enhanced the number of colonies grown in agarose, but the MTT levels and [3H]thymidine incorporation-proliferation (24 h) were reduced. Chemopreventives also increased differentiation defined by the number of cornified cells and the expression of high-molecular-weight keratin-positive cells. Malignant transformation potential was depressed by reducing gamma-glutamyl transpeptidase and mutant p53 expression, whereas tumor suppressor p53 was enhanced. NHKs treated with DMBA and injected into nude mice (nu/nu: 1 x 10(6) cells/0.25 ml) produced tumor masses (3 of 3 animals), whereas the nutrient and DMBA groups produced smaller tumor masses, some with central ulcers (2 of 3 animals). Mock injection of untreated or nutrient-treated NHKs without DMBA treatment did not produce a tumor mass (0 of 3 animals). beta-Carotene, retinyl palmitate, and canthaxanthin increased differentiation and reduced transformation induced by DMBA in oral NHKs.
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PMID:In vitro growth changes of oral human keratinocytes after treatment with carotenoids, retinoid, and/or DMBA. 1022 45

We experienced a rare case of leptomeningeal melanomatosis. The proliferative activity and nuclear accumulation of p53 in this tumor were examined, since the relationship between this tumor type and growth has not yet been elucidated. A 33-year-old Japanese man was shown to have leptomeningeal melanomatosis with multiple cutaneous pigmented nevi. The autopsy findings showed the presence not only of benign diffuse melanosis of the leptomeninges but also of leptomeningeal melanomatosis in the subarachnoid space and brain parenchyma. In the brain parenchyma, the direct invasion of tumor cells from the subarachnoid space and Virchow-Robin spaces filled with melanoma cells were observed. Multiple hemorrhagic areas invaded by melanoma cells were also present. Immunohistochemical staining with a monoclonal antibody to melanoma cells showed positivity in the tumor cells. Proliferation analysis using the MIB-1 antibody demonstrated that the labeling index of tumor cells invading brain parenchyma (2.54%) was higher than that in other lesions of the inner (0.89%) and outer layer (0.76%) of the subarachnoid space. Nuclear accumulation of p53 protein was rarely seen in the tumor cells. We reported a case of leptomeningeal melanomatosis. Higher proliferative activity was found in invading cells of the brain parenchyma. Malignant transformation of the tumor did not appear to be associated with p53 gene mutation.
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PMID:Leptomeningeal melanomatosis with multiple cutaneous pigmented nevi: tumor cell proliferation and malignant transformation in an autopsy case. 1058 67


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