UNIPROT:P04637 - FACTA Search

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

Carcinogenesis requires a complex series of genetic changes often involving multiple oncogenes and the inactivation of multiple tumor-suppressor genes. We presently examined the effect of the Krev-1 tumor-suppressor gene on the tumorigenic and metastatic potential of Ha-ras-transformed cloned rat embryo fibroblast (CREF) cells. Ha-ras-transformed CREF cells are morphologically transformed and anchorage independent; produce reduced levels of nm23-H1 (a putative metastasis-suppressor gene product) and TIMP-1 (tissue inhibitor of metalloproteinase 1) transcripts and mRNA compared with CREF cells; produce increased levels of cripto, 94-kDa gelatinase/type IV collagenase (94-kDa GEL), osteopontin (OPN) and transin/stromelysin transcripts and mRNA compared with CREF cells; and are tumorigenic and metastatic in both nude mice and syngeneic rats. Ha-ras-transformed CREF cells coexpressing the Krev-1 gene display a reversion in cellular phenotype and gene expression to that of untransformed CREF cells. However, Ha-ras/Krev-1-coexpressing CREF cells retain, albeit with extended latency periods, both tumorigenic and metastatic potential that is not related directly to the final level of Ha-ras or Krev-1 mRNA or the Ha-ras p21 transforming protein. Development of metastatic potential is, however, directly correlated with a reduction in nm23-H1 and TIMP-1 transcription and mRNA levels and an enhanced expression of cripto, 94-kDa GEL, osteopontin and transin. In contrast, expression of additional tumor-suppressor genes, such as the RB gene and p53, or genes associated with tumorigenesis in other model systems, such as major excreted glycoprotein (MEP), 72-kDa gelatinase/type IV collagenase (72-kDa GEL), fibronectin (FIB), tenascin and intracellular adhesion molecule 1 (ICAM-1) is not altered in a consistent manner during in vitro transformation suppression or escape from tumorigenic and metastatic suppression. These results indicate that Krev-1 suppression of the Ha-ras-transformed/oncogenic phenotype is associated with a distinct program of gene expression changes manifested by altered rates of transcription and steady-state mRNA levels of specific oncogenic-suppressing and oncogenic-inducing genes. These data support a model of Ha-ras-induced metastasis in CREF cells that involves a direct modulation in the expression/suppression of specific combinations of oncogenic-suppressor genes and metastasis-promoting genes that are regulated coordinately in the process of tumor progression.
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PMID:Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells. 847 44

We investigated the effects of bile acid feeding on the mRNA levels and transcriptional activity of genes involved in various facets of hepatic cell function. Rats were maintained for 10 days on standard diet supplemented with combinations of 1 and 0.4% deoxycholic acid and ursodeoxycholic acid. Significant reductions in mRNA levels for liver fatty acid binding protein, albumin, the asialoglycoprotein receptor, connexins 32 and 26, and cytochromes P-450IIB1 and P-450IIE1 were associated with 1% deoxycholic acid feeding. Conversely, the 1% deoxycholic acid-fed animals exhibited increased mRNA levels for cholesterol 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl-CoA reductase, multidrug resistance, procollagens, extracellular matrix, protooncogenes, tumor suppressors, and cyclins. The 0.4% deoxycholic acid-fed animals exhibited increased mRNA levels for c-jun, H-ras, p53, cyclins D1 and D3, fibronectin, and procollagens alpha 1(I) and alpha 1(III). Transcriptional rate changes could not account for the observed changes in steady-state mRNA levels. Ursodeoxycholic acid feeding had no significant effect on gene expression and almost completely inhibited the changes associated with 1% deoxycholic acid when coadministered. The results indicate that dietary ingestion of deoxycholic acid profoundly affects hepatic gene expression in the rat, and regulation occurs primarily at the posttranscriptional level.
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PMID:Posttranscriptional regulation of mRNA levels in rat liver associated with deoxycholic acid feeding. 857 28

The role of bone marrow stromal cells of the hematopoietic microenvironment in ionizing-irradiation leukemogenesis is a focus of current investigation. Evidence from recent in vitro and in vivo experiments suggests that damage by slowly proliferating cells of the hematopoietic microenvironment contributes to the sustained survival of irradiation-damaged hematopoietic progenitor cells/stem cells and can contribute to the selection and proliferation of a malignant clone. The molecular mechanism of the interaction of irradiated stromal cells with attached hematopoietic cells has been difficult to evaluate. Irradiated bone marrow stromal cell line D2XRII demonstrated altered patterns of fibronectin splicing and increased expression of several transcriptional splice variants of macrophage-colony-stimulating factor. Differential display has revealed specific radiation-induced gene transcripts which persist after irradiation of stromal cells in vitro or in vivo. In recent experiments, we demonstrated that irradiation of mouse bone marrow stromal cell line D2XRII induces release of significant levels of transforming growth factor (TGF)-beta into the tissue culture medium despite the lack of a detectable increase in TGF-beta mRNA. Since TGF-beta is known to induce reactive oxygen species (ROS), we tested how a target hematopoietic cell line, responsive to ROS by up-regulation of a transgene for an antioxidant protein, responded to cocultivation with irradiated bone marrow stromal cells. Bone marrow stromal cell line GPIa/GBL, derived from long-term bone marrow culture of a C57BL/6J-GPIa mouse, was irradiated in vitro and then cocultured with the interleukin (IL)-3-dependent hematopoietic progenitor cell line 32D cl 3, or with each of several subclonal lines expressing a transgene for human manganese superoxide dismutase (MnSOD). Cobblestone island formation, as a measure of adherence and proliferation by 32D-MnSOD clones in the presence or absence of IL-3, was increased with irradiated compared to control GPIa cells. Furthermore, using a fluorescent dye which detects ROS, hematopoietic cells cocultivated with irradiated stromal cells demonstrated higher levels of intracellular ROS than cells cocultivated and forming cobblestone islands on nonirradiated stromal cells. Since ROS are known to induce mutations in hot spots in the p53 gene, it appears worthwhile to investigate a potential mechanism for irradiated stromal cell induction of hematopoietic stem cell transformation through ROS-induced mutations. The present cell culture and molecular biology techniques provide new methods to analyze the effects of irradiated stromal cells on closely attached hematopoietic stem cells during irradiation leukemogenesis.
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PMID:Role of bone marrow stromal cells in irradiation leukemogenesis. 867 55

Granulomas occurring in sarcoidosis with lung involvement are mostly located in the paravasal interstitium, pleura, bronchial mucosa and stroma. The phases and the activity of the disease process are characterised by different patterns from multicellular epitheloidcellular granulomas to marked hyalinisations and scarifications. For the purpose of histochemical characterisation of the composition of the cells and matrix of pulmonary granulomas in open and transbronchial lung biopsies of 15 patients suffering from sarcoidosis in different clinical stages, antibodies were employed against macrophages, neutrophil elastase, collagen types I and III, fibronectin, laminin, PCNA and against the tumour suppressor gene product P53. Identification was subsequently performed either by means of indirect immunofluorescence or the PAP technique. Multicellular granulomas showed, especially centrally, a specific fluorescence for macrophages involving also giant cells, whereas antibodies against neutrophil elastase could be mainly identified peripherally. PCNA and P53 protein were identified in the cytoplasm and partly also in the nuclei of giant cells. Collagen types I and III were mainly expressed pericentrally. Fibronectin was found in numerous multicellular epitheloid cellular granulomas not only in the peripheral collagen network but also centripetally oriented. The scarifying granulomas showed initially increased centripetal deposition of fibronectin followed by an addition of collagen types I and III. Laminin was always present in very small quantities only. The results obtained demonstrate a variable expression of matrix structures in sarcoidosis, dependent on the developmental stages of pulmonary granulomas, this expression being capable of control to some extent with the proportions of epitheloid cells, lymphocytes and macrophages that are present. Tumour suppressor gene p53 positive macrophage giant cells and adhesion molecules such as fibronectin participate in granuloma production to a varying extent.
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PMID:[Characterization of structural and cellular components in pulmonary sarcoidosis granuloma]. 868 5

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

Loss of normal p53 tumor-suppressor gene function is characteristic of the majority of squamous carcinomas. During the course of gene transfer studies in the human squamous carcinoma cell line, A253, which does not express p53 mRNA or protein, we incidentally observed increased levels of p53 expression in up to 20% of clonal cell lines derived from parental A253 cells. p 53-expressing A253 cells (A253-p53) were also isolated by dilutional cloning. Nuclear p53 protein was identified by immunohistochemistry in A253-p53 cells in a wild-type pattern, and p53 mRNA (2.5 kb) was demonstrated by northern blot. Mutational analysis of the p53 gene in A253-p53 cells revealed no evidence for mutations in exons 5-9. A253-p53 cells could be distinguished from native A253 cells by prolonged doubling times (2-5 fold) and by a marked reduction of [3H]-thymidine uptake. Whereas A253 cells were unresponsive to the growth-inhibitory effects of TGF-beta, EGF-stimulated A253-p53 cells responded to TGF-beta with markedly reduced DNA synthetic rates. A253-p53 cells cocultured with A253 demonstrated enhanced cell growth and DNA synthesis rates compared to control A253-p53 cells. Finally, A253-p53 cells show reduced expression of c-fos, fibronectin, thrombospondin and parathyroid hormone-related protein (PTHrP) mRNAs. PTHrP measured by RIA in conditioned medium was approximately 300 pM for A253 but undetectable for A253-p53. We conclude that the A253 cell line contains a subpopulation of cells which express high levels of "wild-type-like" p53 protein. This results in dramatic changes in gene expression and a slower-growing phenotype in vitro.
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PMID:Clonal variation of p53 expression and proliferative phenotype in A253 squamous carcinoma cells. 897 69

Multiple genetic alterations, including concurrent inactivation of RB and p53, occur frequently in several human cancers. To investigate the biological significance of RB and p53 gene inactivations, a wild-type RB or p53 cDNA expression vector regulated by tetracycline was introduced by stable transfection into an osteosarcoma cell line Saos-2, in which both the RB and p53 genes were inactivated. Induction of introduced RB expression resulted in suppression of cell growth, increased percentage of cells at the G0/G1 phase, and enlargement of the cells. Furthermore, activity of alkaline phosphatase was increased and expression of fibronectin was decreased, suggesting the induction of cell differentiation by RB expression. Induction of p53 expression also resulted in significant suppression of cell growth with slight accumulation of cells at the G0/G1 and G2/M phases. The cells were detached from culture dishes and the dead cell fraction increased. Furthermore, condensation of chromatin and DNA fragmentation were observed, suggesting the induction of apoptosis by p53. These results suggest that RB and p53 play different roles in carcinogenesis of osteoblast; RB inactivation releases cells from G0/G1 arrest and suppresses cell differentiation while p53 inactivation assists the cells to proliferate by repressing both apoptosis and cell cycle arrest at G0/G1 and G2/M.
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PMID:Differentiation induced by RB expression and apoptosis induced by p53 expression in an osteosarcoma cell line. 913 82

Animal models have an important role in cutaneous research. The guinea pig has proven to be a useful model in a wide spectrum of these cutaneous studies; however, its usefulness is often compromised by the need for depilation. A euthymic hairless guinea pig (HGP) model avoids the problems associated with depilation. Morphologically, as in human skin, these animals have a multi-cell-layer epidermis. Proliferation kinetic studies, as well as documentation of the degree of immunologic cross-reactivity between available antibodies to human cutaneous antigens, could extend the usefulness of this animal model. We performed a battery of anti-human antibodies on formalin fixed tissue, to a variety of antigens present within the skin and on inflammatory cells. These included CD3, UCHL-1, OPD4, L-26, KP-1, Factor XIIIa, S-100 protein, cytokeratin (AE1, AE3 and CK1), CAM 5.2, vimentin, CD 34, Factor VIII, fibronectin, SM actin, collagen IV, laminin, Bcl-2, p53, Ki-67, and PCNA. Cross-reacting antibodies included: CD3, S-100 protein, cytokeratin (AE1, AE3 and CK1), vimentin, Factor VIII, SM actin, collagen IV, p53, Ki-67, and PCNA. Although this battery of antibodies is limited, the markedly increased staining of Ki-67 and PCNA within keratinocytes in the epidermis as compared to normal human skin reflects a high proliferative rate. In addition, positive staining for p53, Ki-67, and PCNA may be useful in studying effects on cell cycle kinetics and apoptosis.
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PMID:Evaluation of cross-reacting anti-human antibodies in the euthymic hairless guinea pig model (HGP) suggests that the HGP may be a model for the study of proliferative skin disease. 913 82

Although human papillomavirus type 16 (HPV16) E6 protein has a transcription-modulatory activity for a wide variety of viral promoters, a cellular target for this activity of E6 has not yet been identified. In this study, using differential hybridization, we identified a mouse fibronectin (FN) gene as a putative cellular target whose expression is up-regulated by E6. Chloramphenicol acetyltransferase (CAT) assays with mouse and rat FN promoter-CAT fusion constructs indicated that HPV16 E6 transactivates the FN promoters in a p53-independent manner. Deletion and site-specific mutation analyses revealed that transactivation by HPV16 E6 depends upon a cyclic AMP response element (CRE) located at -160 relative to the start site of transcription. Gel retardation assays demonstrated that nuclear extracts from the HPV16 E6-expressing cells, compared to those from parental 10T1/2 cells, have increased binding activity to the CRE. Antibodies against c-Jun and ATF-2 disrupted this binding activity. These data indicate that HPV16 E6 transcriptionally modulates FN gene expression via the CRE by inducing the binding of the protein complexes, probably including c-Jun and ATF-2, to the CRE.
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PMID:Human papillomavirus type 16 E6 protein transcriptionally modulates fibronectin gene expression by induction of protein complexes binding to the cyclic AMP response element. 915 19

Studies in cell culture systems have indicated that oncogenic forms of Ras can affect apoptosis. Activating mutations of Ras occur in approximately 30% of all human tumors and 50% of colorectal carcinomas. Since these mutations appear at early or intermediate stages in multistep journeys to neoplasia, an effect on apoptosis may help determine whether initiated cells progress towards a more neoplastic state. We have tested the effects of K-rasVal12 on apoptosis in transgenic mice. A lineage-specific promoter was used to direct expression of human K-rasVal12, with or without wild-type (wt) or mutant SV-40 T antigens (TAg), in postmitotic villus enterocytes, the principal cell type of the small intestinal epithelium. Enterocytes can be induced to reenter the cell cycle by TAgWt. Reentry is dependent upon the ability of TAg to bind pRB and is associated with a p53-independent apoptosis. Analyses of K-rasVal12 x TAgWt bi-transgenic animals indicated that K-rasVal12 can enhance this apoptosis threefold but only in cycling cells; increased apoptosis does not occur when K-rasVal12 is expressed alone or with a TAg containing Glu107,108two head right arrow Lys107, 108 substitutions that block its ability to bind pRB. Analysis of bi-transgenic K-rasVal12 x TAgWt mice homozygous for wild-type or null p53 alleles established that the enhancement of apoptosis occurs through a p53-independent mechanism, is not attributable to augmented proliferation or to an increase in abortive cell cycle reentry (compared to TAgWt mice), and is not associated with detectable changes in the crypt-villus patterns of expression of apoptotic regulators (Bcl-2, Bcl-xL, Bak, and Bax) or mediators of epithelial cell-matrix interactions and survival (e.g., alpha5beta1 integrin and its ligand, fibronectin). Coexpression of K-rasVal12 and TAgWt produces dysplasia. The K-rasVal12-augmented apoptosis is unrelated to this dysplasia; enhanced apoptosis is also observed in cycling nondysplastic enterocytes that produce K-rasVal12 and a TAg with a COOH-terminal truncation. The dysplastic epithelium of K-rasVal12 x TAgWt mice does not develop neoplasms. Our results are consistent with this finding: (a) When expressed in initiated enterocytes with a proliferative abnormality, K-rasVal12 facilitates progression to a dysplastic phenotype; (b) by diminishing cell survival on the villus, the oncoprotein may impede further progression; and (c) additional mutations may be needed to suppress this proapoptotic response to K-rasVal12.
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PMID:Bi-transgenic mice reveal that K-rasVal12 augments a p53-independent apoptosis when small intestinal villus enterocytes reenter the cell cycle. 921 90

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