Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wnt/beta-catenin pathway and p53 are very common targets for genetic alterations in colorectal cancer, and relationships between them have been reported. Here, we describe the relation between Wnt/beta-catenin signaling and the p53-related gene p73. p73, but not p53, activated a promoter containing the Tcf-binding sequence in Saos-2 cells, and the degree of activation was positively correlated with that on a p53-responsive promoter. Moreover, p73beta enhanced Wnt/beta-catenin signaling synergistically with Wnt-3a or exogenously expressed beta-catenin, unlike p53, and the enhancement was not caused by the accumulation of beta-catenin. These results show that the effects of p73 on Wnt/beta-catenin signaling differ from those of p53.
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PMID:p73beta, a variant of p73, enhances Wnt/beta-catenin signaling in Saos-2 cells. 1132 2

Degradation of several intracellular proteins involved in cell cycle control and tumour growth is regulated by the ubiquitin-dependent multicatalytic protease complex (proteasome). We report that proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leucinal (PSI) was cytotoxic on most human myeloid leukaemia cell lines at IC50 doses ranging from 5 to 25 nmol/l. Additionally, PSI pre-treatment enhanced cytotoxicity by taxol and cisplatinum. PSI was more active on leukaemic than on normal CD34(+) bone marrow progenitors because the 50% growth inhibition of colony-forming unit granulocyte macrophage (CFU-GM) from cases of chronic myelogenous leukaemia (CML) and normal subjects was achieved by 15 nmol/l and 50 nmol/l PSI respectively. PSI killed cells by apoptosis as revealed by ultrastructural changes, nuclear DNA fragmentation, cleavage of poly (ADP-ribose) polymerase (PARP) and of beta-catenin, and was antagonized by ectopic expression of Bcl-2 but not by inactivating mutations of p53. This event was associated with a slight accumulation of Bcl-2, a decrease of Bax but no changes in Bcl-X(L) protein expression at any time point. In Ph(+) cell lines BCR-ABL protein was only down-regulated after 48 h of treatment with 10 nmol/l PSI. Altogether, these results indicate that PSI, alone or in association with other cytotoxic agents, has anti-tumour activity against myeloid malignancies and is more effective on leukaemic than on normal haematopoietic progenitor cells.
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PMID:The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI. 1132 92

Lithium affects development of various organisms and cell fate through the inhibition of glycogen synthase kinase-3 beta and induction of the Wnt/beta-catenin signaling pathway. In this study, we investigated the effects of lithium on primary bovine aortic endothelial cells (BAEC). Lithium treatment of BAEC induced beta-catenin stabilization but failed to activate the transcriptional activity of the beta-catenin/T-cell factor complex. Lithium caused a sustained G(2)/M cell cycle arrest without affecting cell viability. Reversibility of this cell cycle arrest occurred up to 3 days after treatment but was reduced thereafter. Lithium-treated BAEC exhibited a senescent-like morphology with an increase in cells positive for the senescence-associated-beta-galactosidase activity. Lithium also increased the expression of p21(Cip), a cyclin-dependent kinase inhibitor, both at the protein and RNA levels. No change in p21(Cip) mRNA stability was observed, whereas the transcriptional activity of a p21(Cip) promoter-luciferase construct containing p53 binding sites was increased after lithium treatment. Furthermore, lithium caused increased transcription of a reporter gene under the control of a promoter containing the p53 consensus binding sites both in transiently transfected BAEC and in a stably transfected fibroblast cell line. Lithium caused accumulation of p53 protein in BAEC without affecting p53 mRNA levels. Finally, up-regulation of p21(Cip) in response to lithium did not occur in mouse embryonic fibroblasts that were null for p53 alleles, confirming the dependence on a p53 pathway for this lithium effect. These findings demonstrate for the first time that lithium induces also stabilization of the tumor suppressor p53 and reveal a new mechanism that may contribute to the neuroprotective effects of lithium.
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PMID:Lithium inhibits cell cycle progression and induces stabilization of p53 in bovine aortic endothelial cells. 1133 98

Several techniques to determine apoptotic frequencies in tumors have been described. In this study, we report that biochemical detection of enzymatic caspase-3 activity is a simple and quantitative technique to measure apoptosis in colorectal tumor cells. The relevance of the level of apoptosis in colorectal cancer for the clinical course remains unclear. Therefore, we studied the correlation between caspase-3 activity and prognosis of the disease in relation to different factors known to be involved in apoptosis induction. High caspase-3 activity significantly correlated with a higher risk of recurrence and was preferentially found in tumors of the right side of the colon. No correlation was detected between high caspase-3 activity and altered protein expression of p53, beta-catenin, or proteins of mismatched repair genes. This indicates that high caspase-3 activity has no evident correlation with the genetic Wnt-signaling or the mismatch repair mutational pathways. The caspase-3 activity significantly correlated with CD57(+) tumor infiltrating cells. Therefore, high caspase-3 activity in right-sided tumors might be induced by a specific lymphocytic reaction.
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PMID:Caspase-3 activity as a prognostic factor in colorectal carcinoma. 1135 Oct 40

Destruction of beta-catenin is regulated through phosphorylation-dependent interactions with the F box protein beta-TrCP. A novel pathway for beta-catenin degradation was discovered involving mammalian homologs of Drosophila Sina (Siah), which bind ubiquitin-conjugating enzymes, and Ebi, an F box protein that binds beta-catenin independent of the phosphorylation sites recognized by beta-TrCP. A series of protein interactions were identified in which Siah is physically linked to Ebi by association with a novel Sgt1 homolog SIP that binds Skp1, a central component of Skp1-Cullin-F box complexes. Expression of Siah is induced by p53, revealing a way of linking genotoxic injury to destruction of beta-catenin, thus reducing activity of Tcf/LEF transcription factors and contributing to cell cycle arrest.
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PMID:Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. 1138 39

The adenomatous polyposis coli (APC) tumor-suppressor protein, together with Axin and GSK3beta, forms a Wnt-regulated signaling complex that mediates phosphorylation-dependent degradation of beta-catenin by the proteasome. Siah-1, the human homolog of Drosophila seven in absentia, is a p53-inducible mediator of cell cycle arrest, tumor suppression, and apoptosis. We have now found that Siah-1 interacts with the carboxyl terminus of APC and promotes degradation of beta-catenin in mammalian cells. The ability of Siah-1 to downregulate beta-catenin signaling was also demonstrated by hypodorsalization of Xenopus embryos. Unexpectedly, degradation of beta-catenin by Siah-1 was independent of GSK3beta-mediated phosphorylation and did not require the F box protein beta-TrCP. These results indicate that APC and Siah-1 mediate a novel beta-catenin degradation pathway linking p53 activation to cell cycle control.
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PMID:Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. 1138 40

Four different genetic abnormalities may occur in endometrioid adenocarcinomas of the endometrium (mircosatellite instability and mutations in the PTEN, k-RAS and beta-catenin genes), whereas nonendometrioid carcinomas of the endometrium often have p53 mutations and loss of heterozygosity on several chromosomes. Occasionally, a nonendometrioid carcinoma may develop as a result of dedifferentiation of a preexisting endometrioid carcinoma; in such a case, the tumor exhibits overlapping clinical, morphologic, immunohistochemical, and molecular features of the 2 types. The insaturation of microsatellite instability in endometrial carcinogenesis seems to occur late in the transition from complex hyperplasia to carcinoma, and it is preceded by progressive inactivation of MLH-1 by promoter hypermethylation. Moreover, the endometrioid adenocarcinomas that exhibit microsatellite instability show a stepwise progressive accumulation of secondary mutations in oncogenes and tumor suppressor genes that contain short-tandem repeats in their coding sequences. Mutations in the PTEN and k-RAS genes are also frequent in endometrioid adenocarcinomas of the endometrium, particularly in the tumors that exhibit microsatellite instability, whereas beta-catenin mutations do not seem to be associated with such a phenomenon.
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PMID:Molecular pathology of endometrial hyperplasia and carcinoma. 1267 70

Most hepatocellular carcinomas (HCCs) first occur as well-differentiated HCCs, from which poorly differentiated HCC cells develop because of dedifferentiation. In this study, we try to clarify the changes of dedifferentiation and cell proliferative activity and their relationship in small HCCs (less than 3.0 cm in diameter) and try to learn the mechanism of these changes by analysing the expressions and genetic changes of proliferation-related genes p53 and beta-catenin. Of 41 surgically resected small HCCs, 11 were identified to have tumor heterogeneity. DNA from the 11 small HCCs, consisting of 29 intratumoral lesions and 11 noncancerous liver tissues adjacent to HCCs, was extracted from paraffin embedded tissue sections. Exons 5-8 of p53 gene and exon 3 of beta-catenin gene were amplified by polymerase chain reaction and analyzed by direct sequence. The serial sections were also immunostained by anti-Ki-67, p53 and beta-catenin antibody. Immunohistochemistry showed that the p53 overexpression was significantly related to the proliferative activities as evaluated by Ki-67 immunostaining and to the histological differentiation. The expression of beta-catenin was found to be heterogeneously distributed not only in various histological grades of the same tumor but also in areas of the same histological grade. p53 and beta-catenin gene mutations were detected in 1 tumor respectively, both of which were second primary HCCs and also recurred later. The p53 mutation showed the same mutation pattern in heterogeneous subpopulations. beta-catenin mutation was detected only in the less differentiated lesion but not in the well-differentiated lesion of tumor. In conclusion, our findings suggest that there was histological heterogeneity in small but established HCC, which was accompanied by increased proliferative activity and p53 overexpression. The overexpression of beta-catenin may be related to the proliferative activity and dedifferentiation of HCC.
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PMID:Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 AND beta-catenin. 1147 49

Apoptotic cell death is an active process, which is a critical feature of the regulated development of multicellular organisms. Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants, some of which may be neurotoxic. This study investigates the 2,2', 5,5'-tetrachlorobiphenyl (PCB 52) induced apoptosis in human neuronal SK-N-MC cells, and the role of p53 in this response. Upon treatments with PCB 52, time- and concentration-dependent inhibition of the cell viability was observed. PCB 52 also caused apoptosis, as measured by cell morphology and DNA fragmentation. The capability of PCB 52 to induce apoptosis was associated with the proteolytic cleavage of specific target proteins, such as poly(ADP-ribose) polymerase (PARP) and beta-catenin proteins, suggesting the possible involvement of caspases. In general, DNA-damaging agents induce accumulation of the tumor suppressor protein p53, leading cells to either growth arrest in G1, or apoptosis. However, our data showed that both p53 and Bcl-2 protein levels were decreased in a time-dependent manner during apoptosis after exposure to PCB 52. These results suggest that PCB 52 induced a p53-independent apoptosis in these cells.
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PMID:Induction of apoptotic cell death by a p53-independent pathway in neuronal SK-N-MC cells after treatment with 2,2',5,5'-tetrachlorobiphenyl. 1152 76

Aberrant activation of beta-catenin contributes to the onset of a variety of tumors. We report that a tumor-derived beta-catenin mutant induces accumulation and activation of the p53 tumor suppressor protein. Induction is mediated through ARF, an alternative reading frame product of the INK4A tumor suppressor locus, in a manner partially dependent on the transcription factor E2F1. In wild-type mouse embryo fibroblasts, mutant beta-catenin inhibits cell proliferation and imposes a senescence-like phenotype. This does not occur in cells lacking either ARF or p53, where deregulated beta-catenin actually overrides density-dependent growth inhibition and cooperates with activated Ras in transformation. Thus, the oncogenic activity of deregulated beta-catenin is curtailed by concurrent activation of the p53 pathway, thereby providing a protective mechanism against cancer. When the p53 pathway is impaired, deregulated beta-catenin is free to manifest its oncogenic features. This can occur not only by p53 mutations, but also by ablation of ARF expression, as observed frequently in early stages of colorectal carcinogenesis.
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PMID:Deregulated beta-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation. 1153 55


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