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

Levels of the tumour suppressor protein p53 are increased in response to a variety of DNA damaging agents. DNA damage-induced phosphorylation of p53 occurs at serine-15 in vivo. Phosphorylation of p53 at serine-15 leads to a stabilization of the polypeptide by inhibiting its interaction with Mdm2, a protein that targets p53 for ubiquitin-dependent degradation. However, the mechanisms by which DNA damage is signalled to p53 remain unclear. Here, we report the identification of a novel DNA-activated protein kinase that phosphorylates p53 on serine-15. Fractionation of HeLa nuclear extracts and biochemical analyses indicate that this kinase is distinct from the DNA-dependent protein kinase (DNA-PK) and corresponds to the human cell cycle checkpoint protein ATR. Immunoprecipitation studies of recombinant ATR reveal that catalytic activity of this polypeptide is required for DNA-stimulated phosphorylation of p53 on serine-15. These data suggest that ATR may function upstream of p53 in a signal transduction cascade initiated upon DNA damage and provide a biochemical assay system for ATR activity.
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PMID:The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53. 1043 22

Eventually to understand the integrated function of the cell cycle regulatory network, we must organize the known interactions in the form of a diagram, map, and/or database. A diagram convention was designed capable of unambiguous representation of networks containing multiprotein complexes, protein modifications, and enzymes that are substrates of other enzymes. To facilitate linkage to a database, each molecular species is symbolically represented only once in each diagram. Molecular species can be located on the map by means of indexed grid coordinates. Each interaction is referenced to an annotation list where pertinent information and references can be found. Parts of the network are grouped into functional subsystems. The map shows how multiprotein complexes could assemble and function at gene promoter sites and at sites of DNA damage. It also portrays the richness of connections between the p53-Mdm2 subsystem and other parts of the network.
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PMID:Molecular interaction map of the mammalian cell cycle control and DNA repair systems. 1043 23

Interaction of p53 with Mdm2 is hindered if either protein is phosphorylated by DNA-dependent protein kinase (DNAPK), which may account for the activation of p53 in response to double-stranded DNA breaks. This finding raises the question of whether phosphorylation of p53 by DNAPK may have a general effect on its interaction with other proteins. Here we report that unlike the p53/Mdm2 complex, p53/T antigen complex remains intact following phosphorylation by DNAPK, indicating that the effect of phosphorylation upon p53 interaction is dependent on the protein partner. We have previously shown that a mouse p53/T antigen complex can bind DNA in vitro. This complex, however, was significantly reduced in its ability to bind DNA following treatment with DNAPK. This indicates that although phosphorylation did not disrupt the p53/T antigen complex, it did result in a conformational change leading to an alteration of p53' s ability to bind DNA as a protein complex.
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PMID:Phosphorylation by DNAPK inhibits the DNA-binding function of p53/T antigen complex in vitro. 1047 Jan 51

The Mdm2 oncoprotein mediates p53 degradation at cytoplasmic proteasomes and is the principal regulator for maintaining low, often undetectable levels of p53 in unstressed cells. However, a subset of human tumors including neuroblastoma constitutively harbor high levels of wild type p53 protein localized to the cytoplasm. Here we show that the abnormal p53 accumulation in such cells is due to a profound resistance to Mdm2-mediated degradation. Overexpression of Mdm2 in neuroblastoma (NB)(1) cell lines failed to decrease the high steady state levels of endogenous p53. Moreover, exogenous p53, when introduced into these cells, was also resistant to Mdm2-directed degradation. This resistance is not due to a lack of Mdm2 expression in NB cells or a lack of p53-Mdm2 interaction, nor is it due to a deficiency in the ubiquitination state of p53 or proteasome dysfunction. Instead, Mdm2-resistant p53 from NB cells is associated with covalent modification of p53 and masking of the modification-sensitive PAb 421 epitope. This system provides evidence for an important level of regulation of Mdm2-directed p53 destruction in vivo that is linked to p53 modification.
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PMID:Cytoplasmically "sequestered" wild type p53 protein is resistant to Mdm2-mediated degradation. 1048 81

Chordoid glioma of the third ventricle was recently reported as a novel tumor entity of the central nervous system with characteristic clinical and histopathological features (Brat et al., J Neuropathol Exp Neurol 57: 283-290, 1998). Here, we report on a histopathological, immunohistochemical and molecular genetic analysis of five cases of this rare neoplasm. All tumors were immunohistochemically investigated for the expression of various differentiation antigens, the proliferation marker Ki-67, and a panel of selected proto-oncogene and tumor suppressor gene products. These studies revealed a strong expression of GFAP, vimentin, and CD34. In addition, most tumors contained small fractions of neoplastic cells immunoreactive for epithelial membrane antigen, S-100 protein, or cytokeratins. The percentage of Ki-67 positive cells was generally low (<5%). All tumors showed immunoreactivity for the epidermal growth factor receptor and schwannomin/merlin. There was no nuclear accumulation of the p53, p21 (Waf-1) and Mdm2 proteins. To examine genomic alterations associated with the development of chordoid gliomas, we screened 4 tumors by comparative genomic hybridization (CGH) analysis. No chromosomal imbalances were detected. More focussed molecular genetic analyses revealed neither aberrations of the TP53 and CDKN2A tumor suppressor genes nor amplification of the EGFR, CDK4, and MDM2 proto-oncogenes. Our data strongly support the hypothesis that chordoid glioma of the third ventricle constitutes a novel tumor entity characterized by distinct morphological and immunohistochemical features, as well as a lack of chromosomal and genetic alterations commonly found in other types of gliomas or in meningiomas.
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PMID:Chordoid glioma of the third ventricle: immunohistochemical and molecular genetic characterization of a novel tumor entity. 1051

Transgenic mice expressing the c-Myc oncogene driven by the immunoglobulin heavy chain enhancer (Emu) develop B-cell lymphoma and exhibit a mean survival time of approximately 6 months. The protracted latent period before the onset of frank disease likely reflects the ability of c-Myc to induce a p53-dependent apoptotic program that initially protects animals against tumor formation but is disabled when overtly malignant cells emerge. In cultured primary mouse embryo fibroblasts, c-Myc activates the p19(ARF)-Mdm2-p53 tumor suppressor pathway, enhancing p53-dependent apoptosis but ultimately selecting for surviving immortalized cells that have sustained either p53 mutation or biallelic ARF deletion. Here we report that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that spontaneous inactivation of the ARF-Mdm2-p53 pathway occurs frequently in tumors arising in Emu-myc transgenic mice. Many Emu-myc lymphomas sustained either p53 (28%) or ARF (24%) loss of function, whereas Mdm2 levels were elevated in others. Its overexpression in some tumors lacking p53 function raises the possibility that Mdm2 can contribute to lymphomagenesis by interacting with other targets. Emu-myc transgenic mice hemizygous for ARF displayed accelerated disease (11-week mean survival), and 80% of these tumors lost the wild-type ARF allele. All ARF-null Emu-myc mice died of lymphoma within a few weeks of birth. About half of the tumors arising in ARF hemizygous or ARF nullizygous Emu-myc transgenic mice also overexpressed Mdm2. Therefore, Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, cancelling its protective checkpoint function and accelerating progression to malignancy.
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PMID:Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. 1054 52

The Ink4/Arf locus encodes two tumour-suppressor proteins, p16Ink4a and p19Arf, that govern the antiproliferative functions of the retinoblastoma and p53 proteins, respectively. Here we show that Arf binds to the product of the Mdm2 gene and sequesters it into the nucleolus, thereby preventing negative-feedback regulation of p53 by Mdm2 and leading to the activation of p53 in the nucleoplasm. Arf and Mdm2 co-localize in the nucleolus in response to activation of the oncoprotein Myc and as mouse fibroblasts undergo replicative senescence. These topological interactions of Arf and Mdm2 point towards a new mechanism for p53 activation.
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PMID:Nucleolar Arf sequesters Mdm2 and activates p53. 1055 59

Mdm2 is a cellular oncoprotein the most obvious function of which is the down-regulation of the growth suppressor protein p53. It represents a highly phosphorylated protein but only little is yet known about the sites phosphorylated in vivo, the kinases that are responsible for the phosphorylation or the functional relevance of the phosphorylation status. Recently, we have shown that mdm2 is a good substrate for protein kinase CK2 at least in vitro. Computer analysis of the primary amino acid sequence of mdm2 revealed 19 putative CK2 phosphorylation sites. By using deletion mutants of mdm2 and a peptide library we identified the serine residue at position 269 which lies within a canonical CK2 consensus sequence (EGQELSDEDDE) as the most important CK2 phosphorylation site. Moreover, by using the mdm2 S269A mutant for in vitro phosphorylation assays this site was shown to be phosphorylated by CK2. Binding studies revealed that phosphorylation of mdm2 at S269 does not have any influence on the binding of p53 to mdm2.
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PMID:Identification of a CK2 phosphorylation site in mdm2. 1056 90

The p53 tumour suppressor protein is regulated by ubiquitin-mediated proteasomal degradation. In normal cells p53 is constitutively ubiquitylated by the Mdm2 ubiquitin ligase. When the p53 response is activated by stress signals p53 levels rise due to inhibition of this degradative pathway. Here we show that p53 is modified by the small ubiquitin-like protein SUMO-1 at a single site, K386, in the C-terminus of the protein. Modification in vitro requires only SUMO-1, the SUMO-1 activating enzyme and ubc9. SUMO-1 and ubiquitin modification do not compete for the same lysine acceptor sites in p53. Overexpression of SUMO-1 activates the transcriptional activity of wild-type p53, but not K386R p53 where the SUMO-1 acceptor site has been mutated. The SUMO-1 modification pathway therefore acts as a potential regulator of the p53 response and may represent a novel target for the development of therapeutically useful modulators of the p53 response.
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PMID:SUMO-1 modification activates the transcriptional response of p53. 1056 57

Stabilization of p53 in response to DNA damage is caused by its dissociation from Mdm2, a protein that targets p53 for degradation in the proteasome. Dissociation of p53 from Mdm2 could be caused by DNA damage-induced p53 posttranslational modifications. The ATM and ATR kinases, whose activation in response to ionizing radiation (IR) and UV light, respectively, is required for p53 stabilization, directly phosphorylate p53 on Ser-15. However, phosphorylation of Ser-15 is critical for the apoptotic activity of p53 and not for p53 stabilization. Thus, whether any p53 modifications, and which, underlie disruption of the p53-Mdm2 complex after DNA damage remains to be determined. We analyzed the IR- and UV light-induced stabilization of p53 proteins with substitutions of Ser known to be posttranslationally modified after DNA damage. Substitution of Ser-20 was sufficient to abrogate p53 stabilization in response to both IR and UV light. Furthermore, both IR and UV light induced phosphorylation of p53 on Ser-20, which involved the majority of nuclear p53 protein and weakened the interaction of p53 with Mdm2 in vitro. ATM and ATR cannot phosphorylate p53 on Ser-20. We therefore propose that ATM and ATR activate an, as yet unidentified, kinase that stabilizes p53 by phosphorylating it on Ser-20.
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PMID:Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. 1057 Jan 49


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