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

The tumor suppressor p53 protein down-regulates in vitro the expression of several cellular and viral promoters. However, it is not clear whether this down-regulation reflects equivalent modulation of the activity of these promoters in vivo. Here, we propose a suitable system to assess the effect of p53 on gene expression in vivo: the pair of p53 antisense-transfected and parental HeLa cells. The low amount of free wild-type p53 in HeLa cells seems still sufficient for the repression of several promoters that might be derepressed in p53 antisense-transfected HeLa cells. We have used this system for the demonstration both in vivo and in vitro of the repression of the fibronectin (FN) gene promoter by wild-type p53. The protein and mRNA amounts for FN were increased in the p53 antisense-transfected HeLa clones. This was accompanied by the restoration of the FN network in these cells. FN promoter constructs fused to the chloramphenicol acetyltransferase reporter gene were specifically repressed by wild-type p53 in different cell lines. Integrin alpha 5 beta 1 clustering was changed in the sites of focal contacts, most probably representing its relocalization as a consequence of the increased amounts of fibronectin.
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PMID:Down-regulation of fibronectin gene expression by the p53 tumor suppressor protein. 873 72

To understand the specific cell type responsible for the synthesis of basement membrane components of the salivary gland, the effects of transforming growth factor (TGF)-beta 1 on morphological change, cellular proliferation and collagen synthesis were examined in these immortalized duct and myoepithelial cell clones, and the expression forms of their TGF-beta receptors analysed. When TGF-beta 1 was added to the cell clones in vitro, it induced a morphological alteration, with flattening in myoepithelial but not in duct cells. Although the growth of Mv1Lu mink lung epithelial cells was almost completely inhibited by TGF-beta 1, the duct and myoepithelial cells were partially resistant to such inhibition. By immunoblot analysis of immunoprecipitates, p53 was found bound to the simian virus-40 large T antigen, suggesting a functional loss of p53 in regulation of cell-cycle arrest. In the cloned myoepithelial cells but not the duct cells, TGF-beta 1 stimulated the production of type IV collagen. To attempt to understand the distinct responsiveness of cell clones to TGF-beta 1, the expression forms of TGF-beta receptors were examined by affinity cross-linking. Although the intensities of the cross-linked bands of the TGF-beta type II and type III receptors, particularly the type II, were weaker in the duct than the myoepithelial cell clones, the expression of the type II receptor mRNA was consistently detected in both clones. Accordingly, the reduction of TGF-beta 1 binding may have occurred at the post-transcriptional level. These findings imply that the cloned myoepithelial cells but not the cloned duct cells produce type IV collagen in response to TGF-beta 1 through the receptor-mediated signal transduction pathway, which is presumably disrupted in the cloned duct cells.
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PMID:Different signalling pathways involved in transforming growth factor-beta 1-induced morphological change and type IV collagen synthesis in simian virus-40-immortalized normal human salivary gland duct and myoepithelial cell clones. 880 3

We report in this work a human-derived self-assembling polypeptide based on the tetramerization domain of the human transcription factor p53, which can be fused to single-chain Fv Ab (scFv) fragments via a long and flexible hinge sequence of human origin, allowing exploitation of the functional affinity increase of binding to a ligand or cell surface with multimeric binding sites. We have demonstrated the use of this polypeptide by applying it to the construction of a tetrameric scFv against the tumor-associated carbohydrate Ag Lewis Y (Fuc alpha 1-->2Gal beta 1-->4[Fuc alpha 1-->3] GlcNAc beta 1-->3R). For comparison purposes, the corresponding scFv and dimeric mini-antibody, comprising the scFv fused via a flexible murine hinge to an artificial dimerization domain, were also created. The recombinant mini-antibody proteins were expressed in functional form in Escherichia coli and showed the expected m.w. of a dimer and tetramer, respectively. Analysis of Lewis Y-binding behavior by surface plasmon resonance revealed specific but very weak binding of the scFv fragment. In contrast, both dimeric and tetrameric scFv fusion proteins exhibited an enormous gain in functional affinity that was greatest in the case of the tetrameric mini-antibody.
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PMID:Multivalent antibody fragments with high functional affinity for a tumor-associated carbohydrate antigen. 881 7

We previously showed that TGF alpha synergizes with c-myc in mammary tumorigenesis through inhibition of Myc-induced apoptosis. We therefore examined the effects of growth factors on apoptosis induction in several cell lines from MMTV-myc mammary tumors. When EGF was withdrawn or TGF beta 1 was added, cells became apoptotic after 15 h (by ELISA and morphology). Northern and Western analysis revealed high levels of Bax and p53, and low or undetectable levels of Bcl-2 and Bcl-xS under all treatment condition. In contrast, Bcl-xL expression was highest in the presence of EGF or TGF alpha, with a significant reduction upon removal of EGF or exposure to TGF beta. In mouse mammary tumors, the relative Bcl-xL/Bax ratio was higher in TGF alpha/Myc double transgenics than in Myc single transgenics, in agreement with the in vitro data. Our results suggest a role for Bcl-xL in the regulation of apoptosis by EGF and TGF beta in mammary epithelial cells.
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PMID:Role for Bcl-xL in the regulation of apoptosis by EGF and TGF beta 1 in c-myc overexpressing mammary epithelial cells. 885 33

In response to DNA damage, p53 protein accumulates in the cell nucleus causing cells to undergo DNA repair or apoptosis, programmed cell death. Reintroduction of wild-type p53 into tumors with null or mutant p53 offers a novel strategy for controlling tumor growth, by inducing apoptotic death in neoplastic cells. The efficacy of a replication-deficient p53 adenovirus construct was tested against three human breast cancer cell lines expressing mutant p53, MDA-MB-231, -468, and -435. 231 and 468 cells were both highly transduced at a multiplicity of infection of 10. By contrast, 435 cells were rarely transduced. p53 adenovirus-mediated gene therapy was highly effective against 231 and 468 tumor xenografts in nude mice. At a total dose of 2.2 x 10(9) cellular infectious units (CIU), inhibition of 231 tumor growth was 86% (P < or = .01). Thirty-seven percent of that growth inhibition was due to p53, while 49% was adenovirus-specific. Inhibition of 468 tumor growth was 74% (P < or = .001). Forty-five percent of that inhibition was p53-specific, while 28% was adenovirus-specific. The ED50 values for 231 tumors and 468 tumor growth inhibition were 3 x 10(8) CIU and 2 x 10(8) CIU, respectively. Injection of p53 Ad into 231 or 468 tumors induced apoptosis. By contrast, growth inhibition in 435 tumors treated with p53 adenovirus was not significant, probably due to low adenovirus transduction. 231 and 435 cells both expressed high levels of alpha v, beta 1, beta 3, and beta 5 integrin subunits, ruling out lack of the appropriate integrins as the reason for the low infection rate in 435 cells. Our results demonstrate the ability of wild-type p53 to curtail cancerous cell growth in vivo in tumors expressing mutant p53. The ability of beta-gal Ad to infect tumor cells in vitro was generally predictive of in vivo p53 Ad efficacy.
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PMID:Efficacy of p53 adenovirus-mediated gene therapy against human breast cancer xenografts. 908 Jan 22

Transforming growth factory beta (TGF-beta) is a potent growth inhibitor of epithelial cells. One of the strategies used to elucidate the anti-proliferative mode of action of TGF-beta is to find out whether the receptor-generated signals interact with components of the basic machinery of the cell cycle. In this study we examined whether p53 and two other cycle inhibitory genes that can be transactivated by p53 are affected by TGF-beta 1 in epithelial cells. We show that TGF-beta 1 signalling controls the intracellular localization as well as the phosphorylation pattern and the stability of p53 protein. TGF-beta signalling also elevates the expression of p21/waf-1 and gadd45. The observed modifications in the protein suggest that p53 is involved in mediation of TGF-beta 1 growth inhibition. However, in TGF-beta 1 growth inhibited cells, wild type p53 is not required for the accumulation of the two p53 downstream targets p21/waf-1 and gadd45.
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PMID:Modifications of p53 protein and accumulation of p21 and gadd45 mRNA in TGF-beta 1 growth inhibited cells. 921 30

We have established an ovarian cancer cell line (CABA I) from ascitic fluid obtained from a patient with papillary adenocarcinoma of the ovary prior to drug treatment. The epithelial origin of the cell line was confirmed by morphology and by immunofluorescence analysis using anticytokeratin antibodies. Ultrastructural analysis revealed a very irregular membrane surface and a clear cytoplasm rich in electron-lucent vesicles. CABA I cells grow rapidly in culture (doubling time 18 h) in an anchorage-independent manner. Exogenously added beta-estradiol and epidermal growth factor (EGF) treatments did not influence cell growth rate. FACS analysis to determine the phenotypic profile of tumor-associated antigen, membrane receptor, and adhesion molecule expression indicated that the cell line was positive for different members of the c-erbB family, for alpha 6 and beta 1 integrin receptors, and intensively positive for HLA class I antigens and the folate receptor. Molecular characterization revealed no mutations for c-myc and c-k-ras genes, but did detect an exon 5 mutation in the p53 gene. CABA I cells grew poorly as heterotransplants in nude mice, and tumors showed long latency periods. Because early (15-20) and late (55-60) passage cells maintain the same growth and phenotypic characteristics, the CABA I cell line might provide a good in vitro model system to investigate the cellular and molecular events involved in ovarian carcinogenesis.
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PMID:Ultrastructural and phenotypic characterization of CABA I, a new human ovarian cancer cell line. 922 Apr 98

It is known that long-term withdrawal of choline from the diet induces hepatocellular carcinomas in animal models in the absence of known carcinogens. We hypothesize that a choline deficient diet (CD) alters the balance of cell growth and cell death in hepatocytes and thus promotes the survival of clones of cells capable of malignant transformation. When grown in CD medium (5 microM or 0 microM choline) CWSV-1 rat hepatocytes immortalized with SV40 large T-antigen underwent p53-independent apoptosis (terminal dUTP end-labeling of fragmented DNA; laddering of DNA in agarose gel). CWSV-1 cells which were adapted to survive in 5 microM choline acquired resistance to CD-induced apoptosis and were able to form hepatocellular carcinomas in nude mice. These adapted CWSV-1 cells express higher amounts of both the 32 kDa membrane-bound and 6 kDa mature form of TGF alpha compared to cells made acutely CD. Control (70 microM choline) and adapted cells, but not acutely deficient hepatocytes, could be induced to undergo apoptosis by neutralization of secreted TGF alpha. Protein tyrosine phosphorylation is known to protect against apoptosis. We found decreased EGF receptor tyrosine phosphorylation in acutely choline deficient CWSV-1 cells. TGF beta 1 is an important growth-regulator in the liver. CWSV-1 cells express TGF beta 1 receptors and this peptide induced cell detachment and death in control and acutely deficient cells. Hepatocytes adapted to survive in low choline were also resistant to TGF beta 1, although TGF beta 1 receptors and protein could be detected in the cytoplasm of these cells. The non-essential nutrient choline is important in maintaining plasma membrane structure and function, and in intracellular signaling. Our results indicate that acute withdrawal of choline induces p53-independent programmed cell death in hepatocytes, whereas cells adapted to survive in low choline are resistant to this form of apoptosis, as well as to cell death induced by TGF beta 1. Our results also suggest that CD may induce alterations (mutations?) in growth factor signaling pathways which may enhance cell survival and malignant transformation.
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PMID:Diet, apoptosis, and carcinogenesis. 936 18

Transforming growth factor-beta (TGF-beta) regulates cell proliferation positively or negatively. The mitoinhibition by TGF-beta has been attributed to induction of cyclin-dependent kinase (CDK) inhibitors, such as p15/ Ink4B, p27/Kip1, and p21/Waf1 also known as Cip1 and Sdi1. However, the biological process by which TGF-beta exerts the stimulatory effects on cell growth remains poorly understood. Here we report that TGF-beta 1 stimulates DNA synthesis of IMR-90 human embryonic lung fibroblasts but inhibits that of HuCCT1 human cholangiocarcinoma cells, via down- or up-regulation of p21/Waf1, respectively. TGF-beta 1 markedly suppresses IMR-90 cells to express two different kinds of the p21/Waf1 gene transcription factors, the p53 tumor suppressor and the interferon regulatory factor-1 (IRF-1). This is followed by a marked decrease in expression of p21/Waf1 in a manner consistent with the timing of activation of cyclin E-associated kinase, which normally accompanies the G1-S transition in the cell cycle. Contrarily, TGF-beta 1-induced inhibition of DNA synthesis in HuCCT1 cells is preceded by IRF-1-dependent but p53-independent up-regulation of p21/Waf1 expression followed by inactivation of cyclin E-associated kinase. Thus the cell growth stimulation or inhibition by TGF-beta 1 are mediated by the down- or up-regulation of p21/ Waf1, respectively.
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PMID:Transforming growth factor-beta 1 stimulates or inhibits cell growth via down- or up-regulation of p21/Waf1. 961 5

The mouse skin model of chemical carcinogenesis has been very well characterized with respect to epigenetic changes, which occur during tumour cell initiation, promotion and progression. The use of transgenic and gene knock-out mice has contributed greatly to knowledge in this area. The H-ras genetic locus has been shown to undergo multiple genetic changes, including mutagenic activation, amplification of the mutant gene, and loss of the normal allele. These different genetic events lead to thresholds of ras activity which contribute to different stages along the pathway to neoplasia. The genetic and epigenetic events which lead to tumour invasion and metastasis have been less well characterized than studies on tumour initiation and promotion, despite the fact that it is metastases which ultimately kill the animal/patient. In the mouse skin model, loss of p53 contributes to malignant conversion. Gene deletion of the INK4 locus is associated with transformation to a highly invasive spindle cell tumor phenotype. This spindle cell transformation can also be induced in vitro or in vivo by TGF beta 1, possible by synergizing with mutant H-ras. TGF beta can have both positive and negative effects on tumourigenesis, acting early as a tumour suppresser, but later as a stimulator of tumour invasion. It is this latter effect which may be clinically more significant, since many human tumours overexpress TGF beta, yet the majority still retain the intracellular signaling systems necessary for the cell to respond to this growth factor.
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PMID:Genetic events and the role of TGF beta in epithelial tumour progression. 1034 8


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