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)

Dedifferentiated liposarcoma represents a distinct subtype of liposarcoma and is characterized by the presence of abrupt transition from well-differentiated liposarcoma to high-grade pleomorphic sarcoma (mostly MFH-like). A key role for p53 in tumour progression of this subset of liposarcomas has been suggested on the basis of p53 immunopositivity. A series of 14 dedifferentiated liposarcomas has been investigated by analysing the p53 gene and protein together with the p53-related molecules p21Waf1 and mdm2, to verify whether the p53 pathway is involved in the development and progression of this tumour type. The results indicate that the p53 gene is rarely involved in dedifferentiated liposarcoma (7 per cent of cases analysed) and that low percentages of p53 immunopositivity are still compatible with integrity of the p53 gene. This concept is also supported by the observed preservation of p21Waf1 immunoreactivity in all but the p53-mutated cases. By contrast, mdm2 overexpression emerges as the most frequent abnormality in dedifferentiated liposarcoma (57 and 78 per cent of cases in well-differentiated and high-grade areas, respectively).
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PMID:Molecular abnormalities of the p53 pathway in dedifferentiated liposarcoma. 907 97

Recent findings have indicated that TP53 inactivation in sarcomas may result from mutation and/or deletion of the TP53 gene or, alternatively, from binding to the MDM2 gene products. To investigate further a possible role of the two genes in sarcomas, 24 large and deep-seated lipomas and 74 liposarcomas of various subtypes were analysed for mdm2 and p53 overexpression by immunocytochemistry. Nineteen cases of the same series were also molecularly analysed for both MDM2 gene amplification and TP53 mutations, and a further ten cases for non-random chromosomal abnormalities. In the retroperitoneal well-differentiated-dedifferentiated (WD-DD) group, 15/16 WD and 8/8 DD liposarcomas displayed the mdm2+/p53+ phenotype, consistent with MDM2 gene amplification in the absence of TP53 mutations. In the non-retroperitoneal WD-DD group, 5/11 WD liposarcomas also retained the mdm2+/p53+ phenotype whereas all DD liposarcomas showed an immunophenotype and, when assessed, a genotype consistent with mutant TP53. Null mdm2 immunophenotype, coupled with evidence of a specific chromosome translocation t(12;16), was constantly observed in both the usual and the cellular subtypes of myxoid liposarcoma, three cases of which also showed TP53 alterations at the genetic or protein level. Neither mdm2 nor p53 overexpression was observed in the lipomas. The results show the existence of three main pathogenetically distinct groups of liposarcoma. The first retroperitoneal WD-DD group, which represents a novel class of tumours within a single histological category of sarcoma, where MDM2-mediated inactivation of p53 could be related to the pathogenetic mechanism. The second is the non-retroperitoneal WD-DD group, where the TP53 mutations appear to correlate with the dedifferentiation process. The third is the myxoid group, which is characterized by its own unique cytogenetic profile and never shows any involvement of TP53 or MDM2 genes. As for diagnostic significance, the absence of mdm2 and p53 reactivity in lipomas seems to represent a useful marker for differential diagnosis from lipoma-like WD liposarcomas.
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PMID:Distinct mdm2/p53 expression patterns in liposarcoma subgroups: implications for different pathogenetic mechanisms. 907 98

MDM2 is a cellular protein that binds to and inactivates the p53 tumor suppressor protein. Although mdm2 has been shown to function as an oncogene in vitro, all studies to date have assessed MDM2 activities in the presence of p53, implicating p53 inactivation in MDM2-directed transformation. To determine the role of MDM2 in the cell cycle and in tumorigenesis and whether or not this role is dependent on p53, an MDM2 minigene was expressed during gestation and lactation in the mammary gland of both wild-type p53 (p53+/+) and p53 knockout (p53-/-) mice using the bovine beta-lactoglobulin promoter. In six different transgenic mouse lines, deregulated expression of MDM2 inhibited normal development and morphogenesis of the mammary gland, and caused cellular hypertrophy and nuclear abnormalities. These abnormalities included both multinucleated cells and enlarged cells with giant nuclei. Although there were fewer epithelial cells present in the transgenic mammary gland, no apoptosis was observed. Instead, BrdU incorporation and PCNA staining showed that 12%-27% of the transgenic mammary epithelial cells were in S phase at a time when normal cells were terminally differentiated. Analysis of DNA content showed that 30%-45% of the cells were polyploid, with DNA contents up to 16N, indicating that overexpression of MDM2 caused mammary epithelial cells to undergo multiple rounds of S phase without cell division. This phenotype was similar in the p53+/+ and p53-/- background, demonstrating a role for MDM2 in the regulation of DNA synthesis that is independent of the ability of MDM2 to inhibit p53 activity. Additionally, multiple lines of BLGMDM2 transgenic mice developed mammary tumors, confirming that overproduction of MDM2 contributes to tumorigenesis in epithelial cells in vivo.
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PMID:Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. 908 26

A role for p53 in the regulation of multidrug-resistance (MDR) has been postulated as wild-type p53 suppresses and mutant p53 specifically activates the mdr1 promoter. Moreover, changes in p53 expression and/or functions could be implicated in drug resistance. As the parental lymphoblastic CCRF-CEM cell line has been described as expressing a mutated form of p53, we have examined p53 and mdm2 protein levels in the human multidrug-resistant CEM-VLB cell line variant. These drug-resistant CEM-VLB cells, which have increased expressions of mdr1 and P-glycoprotein, displayed p53 and mdm2 protein expressions similar to those observed in their sensitive CCRF-CEM counterparts. Treatment of these drug-resistant cells with non-toxic doses of the resistance-inducing drug vinblastin induced a strong increase in p53 protein and mRNA but was ineffective on mdm2 protein expression, or mdr1 mRNA expression. These data indicate that mutant p53 protein was not overexpressed in these MDR cells. This overexpression could be induced by microtubule-active drug treatment, but, as previously observed in other sensitive cell lines, mutant p53 from these MDR cells was unable to positively regulate mdm2 gene product expression.
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PMID:P53 protein expression in human multidrug-resistant CEM lymphoblasts. 911 32

The p53 tumor suppressor protein is a sequence-specific transcriptional activator of target genes. Exposure of cells to DNA damage results in accumulation of biochemically active p53, with consequent activation of p53-responsive promoters. In order to study how the transcriptional activity of the p53 protein is regulated in vivo, a transgenic mouse strain was generated. These mice harbor the p53-dependent promoter of the mdm2 gene, fused to a lacZ reporter gene. Induction of lacZ activity by DNA damage (ionizing radiation) was monitored in embryos of different p53 genotypes. The transgenic promoter was substantially activated in vivo following irradiation; activation required functional p53. The activation pattern became more restricted with increasing embryo age, as well as with the state of differentiation of a given tissue. Generally, maximal p53 activation occurred in rapidly proliferating, relatively less differentiated cells. A striking extent of haploinsufficiency was revealed-induction of promoter activity was far less efficient in mice carrying only one wild-type p53 allele. This suggests that normal levels of cellular p53 are limiting, and any further reduction already compromises the p53 response significantly. Thus, the activation potential of p53 is tightly controlled in vivo, both spatially and temporally, and an important element in this control is the presence of limiting basal levels of activatable p53.
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PMID:Transgenic mouse model for studying the transcriptional activity of the p53 protein: age- and tissue-dependent changes in radiation-induced activation during embryogenesis. 913 53

Human papillomaviruses (HPVs) express various gene products, such as E6 protein which complexes with the p53 tumor suppressor protein and therefore diminishes p53-related regulatory mechanisms. This interaction is assumed to be HPV type-specific as "high risk" or oncogenic HPV types have more affinity for p53 binding than their "low risk" or non-oncogenic counterparts. Furthermore, HIV infection is believed to activate latent HPV infection and transcription via direct and indirect interaction with HPVs as well as cellular genes and functions. Accordingly, we carried out experiments on biopsies which originated from condylomas ("low risk" HPVs), HIV-positive condylomas (infection with multiple "low risk" and "high risk" HPVs) and anogenital squamous cell carcinomas (SCCs, "high risk" HPV infection). Using reverse transcription PCR (RT-PCR) and western immunoblotting, mRNA and protein levels of p53 and genes regulated by p53, such as mdm2 and WAF1/CIP1 were determined. We found that the presence of HPV can diminish p53 and increase WAF1/CIP1 and mdm2 protein levels. There were no significant differences in this regulation between "low risk" and "high risk" lesions. Our data suggest that these HPV-mediated cellular effects are not type-specific, and they might be part of a viral-cell interaction or represent a cellular defense mechanism against the virus. However, HIV-seropositivity renders HPV lesions containing both "low risk" and "high risk" significantly different. This may be due to the alteration of HPV-controlling cellular pathways by HIV tat and/or activation of cellular pathways different from HIV-negative counterparts. Either possibility is of great interest and needs further verification.
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PMID:p53, WAF1/CIP1 and mdm2 expression in skin lesions associated with human papillomavirus and human immunodeficiency virus. 913 86

The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
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PMID:Mdm2 promotes the rapid degradation of p53. 915 95

The tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.
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PMID:Regulation of p53 stability by Mdm2. 915 96

The mdm2 gene encodes a family of proteins, a subset of which bind p53 and negatively regulate its function as a transcription factor. We now show that an anti-mdm-2 monoclonal antibody, 2A10, recognises a protein present in rabbit reticulocyte lysate which binds murine p53 translated in vitro. Deletion of p53 residues 10-35, which encompass the mdm-2 binding site, abolished binding of this 2A10-reactive protein. Binding was also dependent upon p53 protein conformation and may require nascent p53 polypeptide since binding was lost following conformational shifting of the temperature-sensitive mutant A135V. Previous studies have shown that mdm-2-p53 complexes fail to exhibit detectable sequence-specific DNA binding. However, our present results demonstrate that p53 in complex with an mdm-2-related protein in vitro retained sequence-specific DNA binding capacity. Non-transformed (but not transformed) 3T3 cells were also found to express a similar 2A10-reactive protein, detectable by gel shift analysis of cellular p53 in complex with a specific DNA target. Mdm-2 in rabbit reticulocyte lysate and in normal, non-transformed 3T3 cells may represent constitutively expressed protein. Our results raise the possibility that constitutive mdm-2 may enhance and/or suppress functions of p53 as yet unidentified.
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PMID:Specific p53-DNA complexes contain an mdm2-related protein. 917 97

Compelling evidence indicates that p53 acts as a transcription factor and that this activity is regulated by several factors including subcellular localization and phosphorylation status of the protein. To learn more about how these two processes determine whether p53 becomes activated, we studied the temperature sensitive murine p53, p53val135. At nonpermissive temperatures, p53val135 remains sequestered in the cytoplasm of cells which express it. Electrophoretic mobility shift assays demonstrated that, under these conditions, the protein lacked DNA binding activity. However, by shifting to the permissive temperature, p53val135 became concentrated in the nucleus, hyperphosphorylated, and had acquired the ability to bind DNA in a sequence specific manner. This was accompanied by the induction of two p53 regulated genes, mdm2 and p21waf1, which indicated that p53val135 had become an active transcription factor. Two dimensional gel electrophoresis and tryptic peptide mapping showed that entry into the nucleus resulted in the appearance of new phosphorylated isoforms and that the protein had become extensively phosphorylation at the N-terminus. Notably, phosphorylation at the N-terminus occurred only in the nucleus, whereas phosphorylation at the C-terminus could occur in both the cytoplasm and the nucleus. Based on these observations, we suggest that phosphorylation of p53's N-terminus is compartmentally restricted.
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PMID:Regulation of DNA binding and transactivation in p53 by nuclear localization and phosphorylation. 919 Oct 51


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