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)

p73, a first p53 relative, was recently identified and shown to be monoallelically expressed in a number of different human tissues. To determine the potential role of this gene in human bladder cancer, we investigated p73 expression levels, allelic expression patterns, and analysed p73 mutations in 23 unselected primary invasive bladder cancers with matched normal tissues and in seven bladder cancer cell lines. In a comparison between normal and tumor tissues using quantitative RT-PCR analysis, we found that p73 was overexpressed in 22/23 bladder cancers, sometimes as great as 20-fold. Allelic expression analysis using a C/T polymorphism in exon 2 and a newly identified T/C polymorphism in exon 5 revealed that p73 was biallelically expressed in both normal bladder and cancer tissues, suggesting that p73 is not imprinted in bladder tissue. Mutation screening of the p73 gene in bladder cancer DNAs using denaturing high-performance liquid chromatography analysis and DNA sequencing revealed no tumor-specific mutations in any coding exons of the p73 gene. These data suggest that the p73 is unlikely to be a tumor suppressor gene, but that overexpression of p73 may contribute to tumorigenesis in bladder cancer.
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PMID:Overexpression of the wild type p73 gene in human bladder cancer. 1010 33

Perturbation of p53 protein function is a common, if not universal, finding in human cancer. Tumor suppression by p53 is due, at least in part, to its ability to activate transcription of certain genes involved in cell cycle control and apoptosis (programmed cell death). Two additional members of the mammalian p53 family, p73 and p51, which is also known as p40, p63, KET, or p73L, were recently identified. Both of these proteins share substantial sequence homology with p53 and can, at least when overproduced, activate p53-responsive promoters and induce apoptosis. Nonetheless, data on differences between these proteins and p53 are emerging. For example, p73 is not induced by DNA damage and is not targeted for inactivation by viral oncoproteins such as simian virus 40 (SV40) T antigen, adenovirus E1B 55K, and human papillomavirus E6. In contrast to p53, neither p73 nor p51 appears to be frequently mutated in human cancers on the basis of the limited studies reported to date. Finally, unlike p53, cells produce multiple p73 and p51 isoforms as a result of alternative splicing, and production of p73 and p51 appears to be restricted to certain tissues. Additional studies are required to determine the role, if any, that p73 and p51 play in cell growth control and carcinogenesis.
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PMID:The emerging p53 gene family. 1020 77

The newly identified p53 homolog p73 can mimic the transcriptional activation function of p53. We investigated whether p73, like p53, participates in an autoregulatory feedback loop with MDM2. p73 bound to MDM2 both in vivo and in vitro. Wild-type but not mutant MDM2, expressed in human p53 null osteosarcoma Saos-2 cells, inhibited p73- and p53-dependent transcription driven by the MDM2 promoter-derived p53RE motif as measured in transient-transfection and chloramphenicol acetyltransferase assays and also inhibited p73-induced apoptosis in p53-null human lung adenocarcinoma H1299 cells. MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300/CBP by competing with p73 for binding to the p300/CBP N terminus. Both p73alpha and p73beta stimulated the expression of the endogenous MDM2 protein. Hence, MDM2 is transcriptionally activated by p73 and, in turn, negatively regulates the function of this activator through a mechanism distinct from that used for p53 inactivation.
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PMID:MDM2 suppresses p73 function without promoting p73 degradation. 1020 51

Multiple adenovirus (Ad) early proteins have been shown to inhibit transcription activation by p53 and thereby to alter its normal biological functioning. Since these Ad proteins affect the activity of p53 via different mechanisms, we examined whether this inhibition is target gene specific. In addition, we analyzed whether the same Ad early proteins have a comparable effect on transcription activation by the recently identified p53 homologue p73. Our results show that the large E1B proteins very efficiently inhibited the activity of p53 on the Bax, p21(Waf1), cyclin G, and MDM2 reporter constructs but had no effect on the activation of the same reporter constructs by p73, with the exception of some inhibition of the Bax promoter by Ad12 E1B. The repressive effect of the E1A proteins on p53 activity is less than that seen with the large E1B proteins, but the E1A proteins inhibit the activity of both p53 and p73. We could not detect significant inhibition of p53 functions by E4orf6, but a clear repression of the transcription activation by p73 by this Ad early protein was observed. In addition, we found that stable expression of the Ad5 E1A and that of the E1B protein both caused increased p73 protein expression. The large E1B and the E4orf6 proteins together do not target the p73 protein for rapid degradation after adenoviral infection, as has previously been found for the p53 protein, probably because the large E1B protein does not interact with p73. Our results suggest that the p53 and p73 proteins are both inactivated after Ad infection and transformation but via distinct mechanisms.
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PMID:Distinct regulation of p53 and p73 activity by adenovirus E1A, E1B, and E4orf6 proteins. 1020 12

The p73 gene encodes a protein that shares structural and functional homologies with the p53 tumor suppressor protein. The p73 gene is monoallelically expressed in normal tissue, maps to chromosome 1p36 and is deleted in human neuroblastoma cell lines. Alternative splicing of exon 13 in p73 transcripts generates two isoforms, p73alpha and p73beta, that differ in their carboxy-terminus and in their ability to form homotypic interactions. In this study, we investigated, in 129 human central nervous system tumors of various histological types, the levels of p73 transcripts and the splicing characteristics of p73 mRNA. Whereas p73 mRNA content was consistently low in most tumoral types, especially in meningiomas, some glioblastomas, medulloblastomas and metastases exhibited elevated p73 mRNA content. However, ependymomas expressed consistently high amounts of p73 mRNA, significantly different from the other tumoral types. Whereas the short (p73beta) isoform accounted for 20-25% of the total p73 mRNA in most of the tumors, these splicing characteristics were altered in ependymomas (only 9% of p73beta) and in neurinomas (up to 53% of p73beta). These observations suggest tissular or tumoral differences in the control of p73 gene transcription and alternative splicing, and raise the problem of the role of p73 isoforms in the control of tumor growth, particularly in ependymomas.
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PMID:p73 gene transcripts in human brain tumors: overexpression and altered splicing in ependymomas. 1021 63

SV40 and/or DNA sequences indistinguishable from SV40 have been detected in several types of human tumours. The oncoprotein of Simian virus 40, SV40 large T-antigen (Tag), is known to bind and inactivate tumour suppressor proteins, such as members of the retinoblastoma family and p53, thereby promoting cell transformation. In this study, we used the yeast two-hybrid system to investigate whether the Simian virus 40 (SV40) large T-antigen is able to interact with p73, a noval discovered putative tumour suppressor, that is homologous both structurally and functionally to p53. The yeast two-hybrid system is a genetic method to detect protein-protein-interactions in vivo. Our results suggest that the SV40 large T-antigen is not able to bind p73 in yeast although both proteins are expressed in the transformed yeast strain as was shown by western blot analysis.
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PMID:The yeast two-hybrid system reveals no interaction between p73 alpha and SV40 large T-antigen. 1022 25

The p53 tumour suppressor is a transcription factor that regulates the progression of the cell through its cycle and cell death (apoptosis) in response to environmental stimuli such as DNA damage and hypoxia. Even though p53 modulates these critical cellular processes, mice that lack p53 are developmentally normal, suggesting that p53-related proteins might compensate for the functions of p53 during embryogenesis. Two p53 homologues, p63 and p73, are known and here we describe the function of p63 in vivo. Mice lacking p63 are born alive but have striking developmental defects. Their limbs are absent or truncated, defects that are caused by a failure of the apical ectodermal ridge to differentiate. The skin of p63-deficient mice does not progress past an early developmental stage: it lacks stratification and does not express differentiation markers. Structures dependent upon epidermal-mesenchymal interactions during embryonic development, such as hair follicles, teeth and mammary glands, are absent in p63-deficient mice. Thus, in contrast to p53, p63 is essential for several aspects of ectodermal differentiation during embryogenesis.
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PMID:p63 is a p53 homologue required for limb and epidermal morphogenesis. 1022 93

The p73beta protein shares structural and functional similarities with the tumor suppressor gene product p53. Both proteins activate transcription from p53-responsive promoters. p53's activity is antagonized by the mdm2 protein (also termed hdm2 in human cells). Complex formation between p53 and mdm2 results in p53's transcriptional inactivation and destabilization. Here we show that overexpression of mdm2 reduces p73beta's ability to activate transcription, too. The mdm2 protein forms a specific complex with p73beta in vitro with an efficiency comparable to p53-binding. Further, both p73beta and p53 relocalize a transport-defective mutant of mdm2 from the cytoplasm to the nucleus, arguing that complex formation occurs in vivo as well. Mutational analysis suggests that the interaction between p73beta and mdm2 follows structural principles analogous to the p53-mdm2-complex. Whereas p53 is destabilized in the presence of mdm2, the amount of intracellular p73beta was not detectably reduced by mdm2. The carboxyterminal RING finger domain of mdm2 was found to be required to reduce the intracellular abundance of p53, but it was dispensable for transcriptionally inactivating either p53 or p73beta. Our results suggest that the autoregulatory feedback loop between p53 and mdm2 also controls p73's activity, but that mdm2-mediated protein degradation is unique to p53.
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PMID:Inactivation of the p53-homologue p73 by the mdm2-oncoprotein. 1032 34

p73, the first homologue of the tumour suppressor protein p53, was recently discovered on chromosome 1p36 and has been shown to induce apoptosis in a p53-like manner. The present study was performed with the aim of investigating the expression of p53, its new homologue p73 and the occurrence of apoptosis in cholangiocellular carcinoma. Protein levels of p73 were examined in 41 patients with curatively (R0-) resected cholangiocellular carcinomas with an antiserum, raised against a peptide in the N-terminal domain of p73. The incidence of mutations in the p53 gene was analysed by direct sequencing and also immunohistochemically. Apoptotic cell death was assessed using in-situ end-labelling (ISEL) technique in combination with morphological criteria. The results obtained were correlated with patient survival. Immunostaining of p73 protein was detected in 17/41 carcinomas examined (41%). The immunoreactivity was confined to the cell nucleus. In 15/41 patients (37%), mutations of the p53 gene were observed. Eleven out of these 15 patients stained also positive for p73. In contrast, out of 26 patients without any detectable p53 mutation, only six exhibited p73 immunostaining. We failed to observe a correlation between p73 expression or p53 and apoptosis within a given tumour. Survival analysis including the parameters stage and grade of disease, p73 and p53, and also apoptosis, showed that tumour stage and grade as well as p53 and p73 were significantly related to prognosis. In Cox regression survival analysis, however, only extent of primary tumour and lymph node status had an independent prognostic impact. Our results with a high prevalence of p73 within tumours harbouring mutated p53 gene suggest that p73 could compensate for p53 function. We failed to establish p73 or p53 as independent prognostic factors in cholangiocellular carcinoma of the liver.
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PMID:Expression of p73, a novel protein related to the p53 tumour suppressor p53, and apoptosis in cholangiocellular carcinoma of the liver. 1036 18

p73 is a candidate tumor suppressor gene with substantial DNA and protein homology to the p53 tumor suppressor gene. We have investigated two hypotheses: (a) p73 is mutated in diverse types of human cancer, and (b) p73 is functionally redundant with p53 in carcinogenesis so that mutations would be exclusive in these two genes. The entire coding region and intronic splice junctions of p73 were examined in 54 cancer cell lines. Three lung cancer cell lines contained mutations that affected the amino acid sequence. One amino acid substitution was in a region with homology to the specific DNA binding region of p53 and two microdeletions were outside the region of homology. Two of the cell lines with p73 mutations also carried p53 mutations. Although our results are inconsistent with the two hypotheses tested, p73 mutations may contribute infrequently to the molecular pathogenesis of human lung cancer.
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PMID:Mutational analysis of p73 and p53 in human cancer cell lines. 1036 63


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