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 gene, a new p53 homologue, has been identified: it supposedly acts as tumour suppressor gene in neuroblastoma. To clarify whether p73 might be involved in lung carcinogenesis, we examined p73 expression in resected lung cancer and paired normal lung in 60 cases using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). We also examined p73 gene status in three representative cases using Southern blot, and p53 gene alteration in 49 cases using PCR-single-strand conformation polymorphism (PCR-SSCP) and direct sequence. In 87% of the cases (52/60) p73 expression in tumour was more than twice as high as that in paired normal lung tissues, and the difference between p73 expression in tumour and normal lung tissue was significant (P < 0.0001). However, Southern blot analysis revealed that none of the cases showed p73 gene amplification. Compared with clinicopathological characteristics, p73 expression correlates significantly with histological differences and age of patient, independently (P < 0.05). Concerning p53 gene status, 43% (21/49) showed p53 gene alteration, but there was no correlation between p73 overexpression and p53 gene alteration. Our results suggest that need for further functional analysis of the role of p73 in lung carcinogenesis.
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PMID:The expression of p73 is increased in lung cancer, independent of p53 gene alteration. 1040 9

Accumulating evidence has demonstrated that aberration of the p53 tumour-suppressor gene is one of the pivotal genetic events in hepatocellular carcinogenesis. Recent reports suggest that the product of hepatitis B virus (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein reduces p53 expression. A novel p73 gene, which is related to p53, has recently been identified and mapped to chromosome 1p36.3, which is a locus of multiple tumour-suppressor genes for many cancers, including hepatocellular carcinoma (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and mutation of p73 in 48 HCCs obtained from untreated patients. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was expressed ubiquitously at low levels in all the tumour tissues, as well as in the adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP) analysis showed no mutations in the 48 tumours except for three types of polymorphisms. These results suggest that p73 may play a role in hepatocellular carcinogenesis in a different manner from a Knudson two-hit model. The regulatory mechanism of interaction between p73 and hepatitis viruses remains to be determined.
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PMID:Absence of mutation of the p73 gene localized at chromosome 1p36.3 in hepatocellular carcinoma. 1040 9

The p73 gene is located on 1p36.2-3, a region that is frequently deleted in human cancer. Because p73 encodes for a protein that is both structurally and functionally homologous to the p53 protein, p73 has been postulated to be a candidate tumor suppressor gene. To date, however, mutations of p73 have not been found. To study methylation of the p73 5'CpG island, a human bacterial artificial chromosome clone containing exon 1 and the 5' region of p73 was isolated. There was no evidence for p73 exon 1 methylation in normal tissues. In contrast, p73 was aberrantly methylated in approximately 30% of primary acute lymphoblastic leukemias (ALLs) and Burkitt's lymphomas. There was no evidence for methylation in any other types of hematological malignancies or solid tumors examined. In both leukemia cell lines and primary ALLs, methylation was associated with transcriptional loss of p73 by reverse transcription-PCR. We used single-strand conformational polymorphisms to screen for point mutations in a series of primary ALLs and found no mutations leading to a change in protein structure. Our results show that methylation of p73 is a frequent event in specific types of hematological malignancies and suggest that epigenetic silencing of p73 could have important consequences for cell-cycle regulation.
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PMID:Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5' CpG island methylation. 1041 92

The p73 gene, a member of the p53 family, is a new candidate tumor suppressor gene. To investigate the possibility of genetic alteration of p73 in leukemia and lymphoma, we examined 55 cell lines and 39 patient samples together with 17 nonhematopoietic cancer cell lines. Gene expression of p73 was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cell lines (5 of 7 pre B/B-acute lymphoblastic leukemia [ALL], 13 of 21 T-ALL/lymphoblastic lymphomas [LBL], 9 of 10 B-non-Hodgkin's lymphomas [B-NHL], 8 of 9 acute myelogenous leukemias [AML], 2 of 2 T-NHL, 3 of 3 multiple myeloma), and in patient samples (16 of 23 pre B-ALL, 5 of 8 T-ALL/LBL, 5 of 8 B-NHL). PCR-single-strand conformation polymorphism (SSCP) of cDNAs showed no mutation in 43 p73-expressing cell lines within the regions that corresponded to the 5 mutational hotspots of the p53 gene. Neither homologous deletion nor rearrangement of the p73 gene were found by Southern blot analysis in any of the cell lines that lack expression of p73. In contrast to prior published data, analysis of a polymorphic site showed that the p73 gene was expressed biallelically in cell lines and normal peripheral blood. Notably, the p73-negative cell lines were hypermethylated at a CpG island in the 5' untranslated region of the p73 mRNA, and treatment of these cell lines with 5-azacytidine (5-AC), a demethylation reagent, induced p73 expression. Taken together, we found that a sizable proportion (32%) of ALL/B-NHL cell lines and primary tumors had negligible or limited expression of the p73 gene associated with hypermethylation of the gene. These findings suggest that silencing of the p73 gene by hypermethylation may contribute to development and/or progression of lymphoid neoplasms.
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PMID:Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. 1041 5

The function of the p53 tumor suppressor protein is regulated by interaction with Mdm2, which targets p53 for ubiquitin dependent degradation. We show here that like p53, p73 alpha forms an interaction with Mdm2, both in vitro and in cells, but this does not result in the degradation of the p73 alpha protein. The human papillomavirus E6 protein also fails to degrade p73 alpha, suggesting that the mechanisms governing p73 alpha stability are distinct from those known to regulate p53 stability. However, the interaction of Mdm2 with 73 alpha is sufficient to impede p73 alpha transcriptional function, despite the lack of degradation.
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PMID:Mdm2 binds p73 alpha without targeting degradation. 1043 14

The p53 family of proteins play instrumental roles in mediating the cellular response to stress. The p53-related gene product, p73, occurs as two distinct protein isoforms, referred to as alpha and beta, which differ in the length of the C-terminal region and arise through alternative splicing of the p73 RNA. Here, we describe an analysis of the transcription properties of p73 and show that although there are certain similarities between transcriptional activation mediated by p73 and p53, such as in their sensitivity to adenovirus E1A and the requirement for p300/CBP co-activator proteins, significant differences are apparent in the response mechanisms. Thus, we find that p73 shows a degree of specificity for the promoters of target genes that is quantitatively distinct from the response mediated by p53. For example, p73 activates the GADD45 gene more efficiently than p53, whereas the reverse situation was apparent for the p21 gene. These effects are, in part, due to the influence of a regulatory domain present in the extended C-terminal of the alpha isoform. Moreover, we provide evidence that this domain regulates protein abundance by influencing the proteasome-dependent degradation of p73. These data define a novel level of isoform-specific control in regulating p73 activity, and thereby highlight a significant difference between the mechanisms that govern the transcriptional activity of p53 and p73.
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PMID:Promoter specificity and stability control of the p53-related protein p73. 1043 30

p73 and p63 are two recently cloned genes with homology to the tumor suppressor p53, whose protein product is a key transcriptional regulator of genes involved in cell cycle arrest and apoptosis. While all three proteins share conserved transcriptional activation, DNA-binding and oligomerization domains, p73 and p63 have an additional conserved C-terminal region. We have determined the three-dimensional solution structure of this conserved C-terminal domain of human p73. The structure reveals a small five-helix bundle with striking similarity to the SAM (sterile alpha motif) domains of two ephrin receptor tyrosine kinases. The SAM domain is a putative protein-protein interaction domain found in a variety of cytoplasmic signaling proteins and has been shown to form both homo- and hetero-oligomers. However, the SAM-like C-terminal domains of p73 and p63 are monomeric and do not interact with one another, suggesting that this domain may interact with additional, as yet uncharacterized proteins in a signaling and/or regulatory role.
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PMID:Solution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain. 1044 9

Homologs of the tumor suppressor p53, called p63 and p73, have been identified. The p63 and p73 family members possess a domain structure similar to p53, but contain variable C-terminal extensions. We find that some of the C-terminal extensions contain Sterile Alpha Motif (SAM) domains. SAM domains are protein modules that are involved in protein-protein interactions. Consistent with this role, the C-terminal SAM domains of the p63 and p73 may regulate function by recruiting other protein effectors.
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PMID:p53 Family members p63 and p73 are SAM domain-containing proteins. 1045 16

TP53, the gene that encodes p53, is a well-defined tumor suppressor gene that is frequently mutated in human cancers. Recently, two proteins homologous to p53, termed p73 and p63, were identified. Current data indicate that both p73 and p63, like p53, can induce cell-cycle arrest and apoptosis, suggesting that they might also be tumor suppressors. However, the physiological signals that can regulate p53, for example, DNA damage, have no effect on p73, as tested in several cell lines. Furthermore, the signaling pathways by which p73 (and possibly p63) induces cell-cycle arrest and apoptosis appear to be similar to those of p53, but also have important differences. Thus, the p53 family proteins are closely related but might have distinct physiological functions.
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PMID:The p53 family: same response, different signals? 1046 50

Loss of heterozygosity (LOH) involving the distal part of the short arm of chromosome 1 occurs frequently in ovarian adenocarcinomas but the tumour suppressor gene(s) targeted by this event is unknown. We have used five microsatellite markers in a panel of 56 ovarian adenocarcinomas to determine which part of 1p34 - 36 is the focus of this LOH. LOH was considerably more common at 1p36 (43%) than at 1p34 - 35 (18%), and 11 tumours showed LOH at 1p36 but not at 1p34 - 35. These data strongly suggest the presence of a tumour suppressor gene inactivated in ovarian adenocarcinoma at 1p36. The p53 homologue, p73, has recently been isolated and mapped to 1p36 and therefore is a candidate for this tumour suppressor gene. However, RT - PCR and Western analyses revealed strong expression of p73 in ovarian adenocarcinoma cell lines but very low or undetectable levels in normal ovarian surface epithelial cells. Immunohistochemical analysis of primary ovarian tumours showed that only 3/22 (14%) contained p73 expressing cells. There was no association between 1p36 LOH and p73 expression in ovarian tumours, nor between p73 and p53 expression. These findings strongly suggest that p73 is not the target of 1p36 LOH in ovarian adenocarcinomas but indicate the presence of an, as yet unidentified, tumour suppressor gene in this region that plays an important role in ovarian tumorigenesis.
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PMID:Frequent loss of heterozygosity at 1p36 in ovarian adenocarcinomas but the gene encoding p73 is unlikely to be the target. 1046 9


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