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

Mutations in the tumor suppressor p53 are a common event in hepatocellular carcinoma (HCC). Because HCCs typically occur in livers with chronic injury and impaired function, we have explored the role of wild-type p53 in regulating the growth and differentiation of Hep 3B hepatoma cells, a p53-negative line derived from a liver cancer. Stable Hep 3B cell lines were generated in which inducible p53 was introduced using either a temperature-sensitive mutant (p53val135) or a tamoxifen-regulated p53-estrogen receptor chimera (p53-mERtm-pBabepuro). In both cell lines, induction of transcriptionally active p53 was confirmed by assessing several p53 targets: Mdm2 protein, p21waf1 mRNA and protein, and the cyclin G promoter. Despite marked induction of p21waf1, cells with active p53 failed to undergo growth arrest, which is probably due to the presence of a non-functional retinoblastoma protein (pRb) in these cells. Apoptosis also was not observed, even after prolonged (48 h) serum starvation or exposure to cisplatinum. Lack of apoptosis was correlated with unchanged bax mRNA levels following p53 induction. Additionally, albumin mRNA levels remained unchanged, and there was no change in basal transactivation of a reporter containing the promoter of the haptoglobin gene, encoding an acute phase protein. This suggests that growth arrest may be required to promote liver-specific gene expression. Overall, our data demonstrate that introduction of transcriptionally active p53 does not alter the malignant, dedifferentiated phenotype of Hep 3B hepatoma cells. Hence, not all cancer cells are equally responsive to the re-activation of wild-type 53. The ability of a cancer cell to undergo p53-mediated phenotypic alterations may depend on the retention of functional downstream effector pathways.
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PMID:Resistance to p53-mediated growth arrest and apoptosis in Hep 3B hepatoma cells. 923 78

The ability of p53 to act as a tumor suppressor is tightly correlated with its ability to function as a transcriptional activator at the G1/S-phase cell cycle checkpoint. Previous overexpression studies have indicated simultaneous induction of p53 target genes, despite opposing cellular functions of their protein products. To delineate the response of endoansactivation function to DNA damage in a normal cell, we irradiated early-passage rat embryo fibroblasts with 10 or 50 J/m2 of ultraviolet light (mostly UV-C). We investigated the induction of p53 targets and the response of the cells over 48 h. In this system, northern analysis revealed differential regulation of the p53 targets p21WAFI/CIPI, Mdm2, Ccng (also known as cyclin G) and Bax in accordance with their proposed functions in the cell. The growth suppressor p21WAFI/CIPI was activated initially (within 6 h) after exposure to 10 J/m2, but not after 50 J/m2, in a p53-dependent manner. Both Ccng and Mdm2 were activated later than p21 (12-24 h) after exposure to 10 J/m2. Expression of Bax was increased after exposure to both 10 J/m2 (24 h after UV exposure) and 50 J/m2 (6 h after UV exposure), which correlated well with the apoptosis seen in cells exposed to either dose. These fibroblasts also exhibited a temporary cell cycle arrest (< 8 h) at 10 J/m2. Thus we have investigated the physiological response of the p53 pathway in normal cells and identified a temporal order for induction of p53 targets. We demonstrate that both apoptosis and cell cycle arrest occur simultaneously when cells are treated with UV radiation, indicating that the amount of DNA damage is not the sole determinant of the cellular response.
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PMID:Differential activation of p53 targets in cells treated with ultraviolet radiation that undergo both apoptosis and growth arrest. 925 29

PC12 cells have previously been shown to cease cell division during nerve growth-factor (NGF)-induced differentiation by affecting specific cell cycle proteins. Staurosporine, a protein kinase inhibitor, also causes PC12 cell differentiation, independently of neurotrophins or plasma membrane receptors. We have investigated the relationship of the tumor suppressor protein, p53, and other cell cycle proteins to the antiproliferative effects of NGF and staurosporine in PC12 cells. NGF treatment of PC12 cells stimulated an increase of p53 protein in the nucleus and, more slowly, an increase in total cellular p53 protein. Levels of the cyclin-kinase inhibitor p21/WAF1, cyclin D1, and cyclin G, all downstream transcriptional targets of p53, increased after short times of NGF treatment. Cessation of replication and differentiation occurred more rapidly in defined medium (2 days) than in serum medium (6 days), in correspondence with the more rapid changes in both p53 and p21/WAF1 levels in defined medium (1 hour) than in serum (1 day). Levels of p34cdc2 and p33cdk2 kinase dropped after 6 to 10 days treatment with NGF in serum, close to the time of terminal differentiation. Staurosporine, on the other hand, inhibited DNA replication of PC12 cells in a time- and dose-dependent fashion by affecting cyclin-dependent kinases. Staurosporine had no effect on the protein levels of p53, p21/WAF1, or cyclin G. The kinase activity of both p34cdc2 and p33cdk2 were inhibited in vitro with IC50 values of 20 nM and 75 nM, respectively. In vivo p34cdc2 kinase activity was inhibited within 1 day, before the decrease in the levels of p34cdc2 protein at days 2 to 3. In contrast, in vivo p33cdk2 kinase activity only decreased in concert with protein levels. Although both NGF and staurosporine inhibit DNA replication concomitant with induction of differentiation by affecting the activity of p34cdc2 and p33cdk2, the mechanism of the two agents is quite different. NGF achieves inhibition of activity of these cyclin-dependent kinases by signalling through the TrkA receptor to the tumor suppressor protein p53 and then to p21/WAF1. In contrast, staurosporine directly inhibits the activity of p34cdc2 and p33cdk2 by binding to them and also indirectly by alteration of their phosphorylation through other regulatory kinases.
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PMID:Different mechanisms for inhibition of cell proliferation via cell cycle proteins in PC12 cells by nerve growth factor and staurosporine. 928 22

Serial analysis of gene expression (SAGE) allows for a quantitative, representative, and comprehensive profile of gene expression. We have utilized SAGE technology to contrast the differential gene expression profile in rat embryo fibroblast cells producing temperature-sensitive p53 tumor suppressor protein at permissive or non-permissive temperatures. Analysis of approximately 15,000 genes revealed that the expression of 14 genes (P < 0.001, > or = 0.03% abundance) was dependent on functional p53 protein, whereas the expression of three genes was significantly higher in cells producing non-functional p53 protein. Those genes whose expression was increased by functional p53 include RAS, U6 snRNA, cyclin G, EGR-1, and several novel genes. The expression of actin, tubulin, and HSP70 genes was elevated at the non-permissive temperature for p53 function. Interestingly, the expression of several genes was dependent on a non-temperature-sensitive mutant p53 suggesting altered transcription profiles dependent on specific p53 mutant proteins. These results demonstrate the utility of SAGE for rapidly and reproducibly evaluating global transcriptional responses within different cell populations.
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PMID:SAGE transcript profiles for p53-dependent growth regulation. 928 62

The gene coding p53 is commonly affected by deletions, rearrangements, or point mutations in a variety of human cancers. p53 is a nuclear phosphoprotein. Mutations are frequently found at highly conserved residues of the p53 protein. The mutant p53 proteins examined so far each have a much longer half-life than that of the wild-type p53 protein which is rapidly degraded under normal conditions. Alterations of p53 protein conformation result in the accumulation of such protein usually in transformed cells or cancer cells. The p53 protein is a sequence-specific DNA-binding protein that is active as a transcription factor. The genes coding p21, GADD45, mdm2, cyclin G etc. contain such a p53 responsive element. Upon exposure of cells to ionizing radiation, ultraviolet light, or DNA-damaging agents, high levels of p53 accumulate, resulting in subsequent stimulation of a series of p53-responsive genes and cell cycle arrest or apoptosis. The function of p53 is also linked to DNA synthesis via interaction with p21 and PCNA. The pathways involving p53 seem to be extremely complicated but may play an important role in the core function of cell growth.
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PMID:[p53]. 930 29

The tumor suppressor p53 can exert its anti-oncogenic activity in part by inducing apoptosis in cells that have sustained damage to their DNA. It is likely that p53 activates the transcription of target genes that mediate this response. Known p53 targets with potential roles in cell cycle control and apoptosis induction include: p21WAF1/CIP1, mdm2, cyclin G, bax and Fas. We examined the p53 pathway in the thymus of the mouse after irradiation. FACS analysis demonstrated that the thymocytes of mice with wild-type p53, but not those lacking p53, underwent apoptosis after irradiation. Expression analysis of the target genes revealed that all tested genes underwent p53-dependent induction, although the extent and timing varied. The target genes implicated in cell cycle (p21, mdm2 and cyclin G) were induced 2 h after irradiation, in contrast to targets with a possible role in apoptosis (bax and Fas), which were induced at 4 h. This analysis is the first demonstration that Fas is a p53-responsive gene in vivo. Since p21 and bax expression are not required for p53-dependent apoptosis, we tested whether other target genes affected apoptosis in vivo. We discovered that mdm2 has no role in preventing apoptosis independently of p53 inactivation, and that Fas, like p21 and bax, is not necessary for p53-mediated induction of apoptosis. Therefore, no p53 target identified and tested to date is singly responsible for p53-dependent apoptosis in response to DNA damage in vivo.
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PMID:The p53 targets mdm2 and Fas are not required as mediators of apoptosis in vivo. 938 Apr 4

The DG75 Burkitt lymphoma-derived human B cell line is heterozygous for p53, carrying wild type (WT) and mutant (Arg283His) alleles. The cells constitutively express high levels of both p53 proteins and also Mdm2. Arg283His transactivates the p21Waf1, Mdm2, bax, cyclin G and IGF-BP3 promoters in transient transfection assays equally as well as, if not better than WT p53. It also suppresses the outgrowth of SAOS-2 cells and specifically binds DNA like wild type protein. However, in primary rodent fibroblasts Arg283His fails to suppress transformation by HPV16-E7 and (Ha-)ras and even has modest transforming activity when transfected alone with (Ha-)ras. When Arg283His is transiently transfected into SAOS-2 cells it efficiently induces apoptosis, so - unlike mutants such as Arg175Pro - its behaviour in transformation assays does not clearly correlate with loss of the apoptosis function. Immunofluorescence staining of both REF transformants and transiently transfected SAOS-2 revealed that this unusual mutant becomes excluded from the nucleus and produces striking cytoplasmic fluorescence. The best correlation with transformation, therefore, appears to be the lack of nuclear retention of Arg283His. Since this mutation does not map to any known nuclear localization signal and its presence seems to result in aberrant exclusion from the nucleus, then it may prove very useful in exploring mechanisms involved in the nuclear:cytoplasmic shuttling of p53.
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PMID:A transforming p53 mutant, which binds DNA, transactivates and induces apoptosis reveals a nuclear:cytoplasmic shuttling defect. 952 42

In this study, using a cell line that carries endogenous wild-type p53 genes, we show that transfection of cells with mutant p53, HPV16-E6, or cyclin G transgenes results in the disruption of higher-order chromatin structure, as evidenced by enhanced sensitivity to micrococcal nuclease. Multiple mechanisms may contribute to this phenotype, including histone H1 phosphorylation, direct binding of oncoproteins to nuclear matrix attachment sites, and altered expression of component genes of the p53 pathway, whose products may function in maintenance of chromatin structure.
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PMID:Chromatin relaxation by overexpression of mutant p53, HPV16-E6, or cyclin G transgenes. 966 21

Erythroleukemia induced by the anemia strain of Friend virus occurs in two stages. The first stage results in rapid expansion of pre-leukemic proerythroblasts (FVA cells) dependent on erythropoietin (Epo) for differentiation and survival in vitro. The second stage is characterized by emergence of erythroleukemic clones (MEL cells) which typically bear activation of the ets-oncogene, PU.1/spi.1, and loss of functional p53. We developed a Friend virus-sensitive, p53-deficient mouse model to investigate the biological advantage conferred by p53-loss during tumor progression. Here we report p53 was not required for cell survival or growth arrest during differentiation of FVA cells, nor was p53 required for induction of apoptosis upon Epo withdrawal. However, we detected induction of the p21Cip1 cyclin-dependent kinase inhibitor gene during differentiation, which was markedly enhanced in the presence of p53. p53-dependent expression of p21Cip1 occurred in the absence of an increase in p53 mRNA and protein levels and was specific for p21Cip1, since expression of gadd45, mdm-2, cyclin G and bax were unaffected by p53. In contrast, treatment of FVA cells with DNA damaging agents led to rapid accumulation of p53 protein resulting in transcription of multiple p53-regulated genes, leading to either apoptosis or growth arrest, depending on the agent used. These data demonstrate that p53-dependent activities during differentiation of preleukemic erythroblasts are distinct from those observed in response to genotoxic agents. We propose that enhancement of p53-dependent gene expression during differentiation may represent a tumor suppressor function which is necessary to monitor differentiation of preleukemic cells and which is selected against during tumor progression.
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PMID:Endogenous p53 regulation and function in early stage Friend virus-induced tumor progression differs from that following DNA damage. 976 22

Cyclin G1 is a recently cloned transcriptional target of p53, it is located in neurons and ventricular ependymal cells and is elevated in neurons after axotomy and cerebral ischemia. The biological function for cyclin G1 in differentiated neurons has thus far not been elucidated. Recently, cyclin G1 has been shown to interact with the B' subunits of serine/threonine protein phosphatase 2A (PP2A) in a rat fibroblast cell line [K. Okamoto, C., Kamibayashi, M. Serrano, C. Prives, M.C. Mumby, D. Beach, p53-dependent association between cyclin G and the B' subunit of protein phosphatase 2A, Mol. Cell. Biol. 16 (1996) 6593-6602]. To further explore whether a similar interaction between cyclin G1 and PP2A B' subunits exists in the central nervous system, the present study compared the regional and developmental expression pattern, subcellular distribution and complex formation between cyclin G1 and the PP2A B' regulatory subunits in the rat brain. In situ hybridization of cyclin G1 and the B'alpha and B'beta subunits of PP2A showed an overlapping distribution in neurons of the cerebral cortex, hippocampus and thalamus at embryonic and early postnatal ages, but their developmental regulation differed. Whereas mRNA and protein levels of PP2A B' subunits were high in the cortical plate, subiculum, hippocampal areas and thalamus at E20 and decreased with age, those of cyclin G1 increased with age and were maximal in the adult cortex and hippocampus. In rat 14-day-old embryonic cortical cultures, cyclin G1 and PP2A B'alpha protein co-localized in nuclear and perinuclear areas of neurons, and both proteins were highly expressed in nuclei of cortical and hippocampal pyramidal cells and the mitral cell layer of the neonatal olfactory bulb. Both cyclin G1 and the PP2A regulatory B'alpha subunits were specifically expressed in neurons and not in glial cells. Antibodies raised against the B'alpha subunits of PP2A immunoprecipitated cyclin G1 in adult cortical lysates, indicating the presence of a complex involving cyclin G1 and the B'alpha subunits of PP2A. This study shows that the regional and subcellular localization of PP2A B' regulatory subunits and cyclin G1 are very similar at early postnatal stages. We discuss the possible functions of a cyclin G1-PP2A B'alpha complex in neurons.
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PMID:Developmental expression and co-localization of cyclin G1 and the B' subunits of protein phosphatase 2a in neurons. 988 95


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