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 aim of the study was to analyze p53 gene mutations and the expression of p53 and mdm2 proteins in 31 randomly selected invasive breast carcinomas. The results were then correlated with tumor grade, stage, estrogen receptor status, nodal status, and DNA ploidy. The expression of the proteins p53 and mdm2 was determined immunohistochemically using formalin-fixed, paraffin-embedded material. Screening for p53 mutation involved analysis of the highly conserved regions of the p53 gene (exons 5-9) by the polymerase chain reaction/ single-strand conformation polymorphism (PCR-SSCP) technique. PCR products with band shifts were directly sequenced. Immunohistochemical staining of p53 was positive in 9 cases (29.0%), only 2 of which showed a p53 gene mutation. These were identified as a C-->G transversion at the second position of codon 278 in exon 8 and an A-->G transition at the second position of codon 205 in exon 6. A third case with a mutation was observed (C-->T transition, position 1 of codon 250 in exon 7) that did not show p53 immunohistochemically. Of the 9 p53-positive tumors, 2 were moderately differentiated (grade II). The remaining tumors were poorly differentiated (7/9). By contrast, p53-negative carcinomas were well differentiated (grade I) in most cases (P = 0.02). DNA cytometry in 8 of the 9 p53-positive carcinomas revealed an aneuploid stem line. The majority of the p53-negative tumors were diploid (P = 0.01). Mdm2 oncoprotein was detected in 10 tumors (32.2%), 4 of which were p53-positive, including the 3 with mutations. The grading of the mdm2-positive tumors was moderate or poor, G1 carcinomas were always noted to be mdm2-negative (P = 0.04). Overexpression of p53 protein is a complex mechanism and does not merely indicate the detection of mutations in the p53 gene. This study has shown that p53 expression correlates with tumor grade and DNA ploidy. Mdm2 expression was also associated with the tumor grade. Immunohistological demonstration of the p53 protein alone is insufficient as a basis for comment on the functional state of the p53 gene and gene product. The interrelation between recognition of the p53 protein and gene mutation needs more careful assessment to define their roles in the control of neoplasia.
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PMID:p53 gene mutations and expression of p53 and mdm2 proteins in invasive breast carcinoma. A comparative analysis with clinico-pathological factors. 926 May 91

The Mdm2 gene is overexpressed in several human tumors. The oncogenic potential of Mdm2 is partially explained by the inhibition of the activity of the tumor suppressor protein p53. Determination of the three-dimensional structure of complexes between Mdm2 and the N-terminal p53 peptide provided a molecular basis for the inhibition of the transcriptional function of p53 by Mdm2. More dramatically, p53 is targeted by Mdm2 for rapid degradation. The Mdm2 gene itself is activated by p53, which gives the opportunity for feed-back control of p53 activity. Keeping p53 under control is most likely the major task of Mdm2 during early development. Recently, evidence was provided for an alternative, p53-independent function of Mdm2.
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PMID:Mdm2: keeping p53 under control. 928 54

The tumour suppressor protein p53 is expressed at very low levels in normal cells but accumulates in response to DNA damaging agents such as u.v. irradiation. This increase is accompanied by transcriptional upregulation of the expression of a number of proteins including Mdm2 which can in turn inhibit p53 dependent transcriptional activation, creating a feedback loop resulting in down-regulation of p53 activity. Mutant p53 proteins are however frequently detected at constitutively high levels in many tumours and tumour cell lines, indeed this phenomenon has been used in several studies to diagnose p53 mutation in patient tumours. We show here that expression of mouse mutant p53 in tumour cell lines of this type results in high levels of both the endogenous p53 protein and the exogenously expressed mutant mouse protein, whereas the human tumour line MCF7 does not exhibit high levels of either endogenous human or exogenously expressed mouse mutant p53 unless stabilisation is induced by DNA damage. This suggests that the stability of mutant p53 is not intrinsic to mutant p53 protein structure but may vary in different cell backgrounds. We present evidence that p53 protein stability in tumour cell lines is determined by association with the Mdm2 tumour suppressor protein, and that p53 mutants which are unable to bind Mdm2 are stable in MCF7 cells. We propose that tumour lines which express high levels of transcriptionally inactive mutant p53 are unable to induce the expression of the Mdm2 protein which would normally provide a feedback mechanism down-regulating p53 protein levels in the absence of DNA damage signals. MCF7 cells however express a transcriptionally active p53 and retain the feedback regulation of p53 protein levels by Mdm2.
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PMID:p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. 929 11

Thrombopoietin (Tpo) has proliferative and maturational effects on immature and more committed cells, respectively. We previously reported a role for Tpo as a survival factor in the factor-dependent human cell line M07e by demonstrating that Tpo suppresses apoptosis in the absence of induced proliferation. Wild-type p53 is a tumor suppressor gene that can play a vital role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. Wild-type p53 can switch from a suppressor conformation, with an antiproliferative, pro-apoptotic phenotype, to a promoter conformation that has a diminished ability to mediate cell cycle arrest and apoptosis. In an effort to elucidate the mechanisms through which Tpo suppresses apoptosis, we investigated the effects of Tpo treatment on p53-mediated apoptosis in M07e cells. Tpo upregulated the expression of the promoter conformation of p53 in M07e cells coincident with a downregulation of Bax and Mdm2 protein levels. Protein levels of Bcl-2 and Bcl-xL did not significantly vary as a function of growth-factor stimulation. Conversely, the levels of suppressor conformation p53 were maximal when M07e was in a growth arrested state and decreased during factor stimulation. Furthermore, Tpo treatment induced an extranuclear buildup and greatly weakened the DNA binding capacity of p53. p53-specific antisense oligonucleotide treatment recapitulated the effects of Tpo treatment on the levels of Bax, Mdm-2, and Bcl-2. These results suggest that Tpo is suppressing growth factor withdrawal induced-apoptosis, at least in part, by downregulating the expression of pro-apoptotic Bax protein levels, through modulating the conformation of p53, which results in a functional inactivation of its pro-apoptotic abilities.
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PMID:Thrombopoietin upregulates the promoter conformation of p53 in a proliferation-independent manner coincident with a decreased expression of Bax: potential mechanisms for survival enhancing effects. 937 50

The cellular response to DNA damage is coordinated by the p53 protein. Mdm2, an oncoprotein, inhibits p53 and promotes p53 degradation. A recent high-resolution structure of the Mdm2-p53 complex may aid the design of small molecules to disrupt this interaction, for use in investigating the interaction further and for designing anticancer drugs.
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PMID:A closer view of an oncoprotein-tumor suppressor interaction. 938 32

Basic fibroblast growth factor (bFGF) can exert mitogenic and viability-promoting effects in a wide range of biological systems. The biochemical activities mediating the cell survival function of bFGF are largely unknown. We report here that exposure of fibroblasts to bFGF, which confers upon them increased survival, also causes at the same time an increase in cellular levels of the Mdm2 oncoprotein. Cells constitutively exposed to a bFGF autocrine loop are more refractory to killing by cisplatin. This increased chemoresistance coincides with elevated Mdm2 and reduced activation of the endogenous p53, resulting in inefficient transcriptional activation of the bax gene promoter. Importantly, unlike Mdm2 accumulation in fibroblasts exposed to DNA damage, induction of Mdm2 by bFGF does not occur through a p53-mediated pathway. The role of p53 in DNA damage-induced apoptosis and the ability of Mdm2 to block p53-mediated cell death are well established. These findings therefore suggest that induction of Mdm2 and the subsequent inhibition of p53 function may contribute, at least partially, to the anti-apoptotic effects of bFGF and possibly some other survival factors.
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PMID:Induction of Mdm2 and enhancement of cell survival by bFGF. 940 Sep 98

p53 tumor suppressor protein negatively regulates cell growth, mainly through the transactivation of its downstream target genes. As a sequence-specific DNA binding transcription factor, p53 specifically binds to a 20-bp consensus motif 5'-PuPuPuC(A/T) (T/A)GPyPyPyPuPuPuC(A/T)(T/A)GPyPyPy-3'. We have now identified, partially purified, and characterized an additional approximately 40-kDa nuclear protein, p53CP (p53 competing protein), that specifically binds to the consensus p53 binding sites found in several p53 downstream target genes, including Waf-1, Gadd45, Mdm2, Bax, and RGC. The minimal sequence requirement for binding is a 14-bp motif, 5'-CTTGCTTGAACAGG-3' [5'-C(A/T)(T/A)GPyPyPyPuPuPuC(A/T)(T/A)G-3'], which includes the central nucleotides of the typical p53 binding site with one mismatch. p53CP and p53 (complexed with antibody) showed a similar binding specificity to Waf-1 site but differences in Gadd45 and T3SF binding. Like p53, p53CP also binds both double- and single-stranded DNA oligonucleotides. Important to note, cell cycle blockers and DNA damaging reagents, which induce p53 binding activity, were found to inhibit p53CP binding in p53-positive, but not in p53-negative, cells. This finding suggested a p53-dependent coordinate regulation of p53 and p53CP in response to external stimuli. p53CP therefore could be a third member of the p53 family, in addition to p53 and p73, a newly identified p53 homolog. p53CP, if sequestering p53 from its DNA binding sites through competitive binding, may provide a novel mechanism of p53 inactivation. Alternatively, p53CP may have p53-like functions by binding and transactivating p53 downstream target genes. Cloning of the p53CP gene ultimately will resolve this issue.
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PMID:p53CP, a putative p53 competing protein that specifically binds to the consensus p53 DNA binding sites: a third member of the p53 family? 940 85

We examined the clinical value of immunohistochemical (IHC) Mdm2 detection by an N-terminal (IF2) and a C-terminal (19E3) binding monoclonal antibody (Ab) in soft tissue sarcomas (STSs) with regard to the p53 status. Therefore, we investigated a cohort of 198 patients with STSs of six entities with known p53 IHC by using a multivariate Cox regression model to determine the prognostic value of Mdm2 staining. Only positivity with the 19E3 Ab correlated multivariately significantly with survival (RR = 2.32, p = 0.0035). We stratified the C-terminal Mdm2 staining (19E3) according to p53 IHC (DO-1) and found patients could be divided into three groups with an increasing risk: (a) patients with Mdm2 (19E3)-negative as well as p53 (DO-1)-negative tumors, (b) patients with tumors that were either Mdm2 (19E3) or p53 (DO-1) positive, and (c) patients with tumors that were Mdm2 (19E3) as well as p53 (DO-1) positive. Positive staining for both Mdm2 and p53 meant a very poor prognosis with a relative risk of 4.63 (p = 0.00001). This points to the possibility that--in addition to the p53-dependent pathway--Mdm2 could have an effect through a p53-independent pathway. Thus, our results indicate that C-terminal Mdm2 staining (19E3) constitutes an independent prognostic marker in STS.
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PMID:Prognostic relevance of C-terminal Mdm2 detection is enhanced by p53 positivity in soft tissue sarcomas. 945 82

Previous work has demonstrated a role for E2F transcription factor activity in the regulation of cell growth during the G0/G1-S phase transition. Indeed, overexpression of E2F proteins, including the E2F1 and E2F2 products, induces DNA synthesis in quiescent fibroblasts. Other experiments have shown that E2F1 expression also induces apoptosis, dependent on p53. Although this could represent a response to aberrant cell cycle progression, we show that only E2F1 induces apoptosis and that this coincides with an ability of E2F1 to induce accumulation of p53 protein. We also find that coexpression of Mdm2, which is known to regulate p53 activity, blocks the E2F1-mediated induction of apoptosis and also blocks the E2F1-mediated accumulation of p53. We propose that E2F1 acts as a specific signal for the induction of apoptosis by affecting the accumulation of p53, which under normal proliferative conditions may be controlled by Mdm2.
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PMID:E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. 948 47

The DG75 Burkitt lymphoma-derived human B cell line is heterozygous for p53, carrying wild type (WT) and mutant (Arg283His) alleles. The cells constitutively express high levels of both p53 proteins and also Mdm2. Arg283His transactivates the p21Waf1, Mdm2, bax, cyclin G and IGF-BP3 promoters in transient transfection assays equally as well as, if not better than WT p53. It also suppresses the outgrowth of SAOS-2 cells and specifically binds DNA like wild type protein. However, in primary rodent fibroblasts Arg283His fails to suppress transformation by HPV16-E7 and (Ha-)ras and even has modest transforming activity when transfected alone with (Ha-)ras. When Arg283His is transiently transfected into SAOS-2 cells it efficiently induces apoptosis, so - unlike mutants such as Arg175Pro - its behaviour in transformation assays does not clearly correlate with loss of the apoptosis function. Immunofluorescence staining of both REF transformants and transiently transfected SAOS-2 revealed that this unusual mutant becomes excluded from the nucleus and produces striking cytoplasmic fluorescence. The best correlation with transformation, therefore, appears to be the lack of nuclear retention of Arg283His. Since this mutation does not map to any known nuclear localization signal and its presence seems to result in aberrant exclusion from the nucleus, then it may prove very useful in exploring mechanisms involved in the nuclear:cytoplasmic shuttling of p53.
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PMID:A transforming p53 mutant, which binds DNA, transactivates and induces apoptosis reveals a nuclear:cytoplasmic shuttling defect. 952 42


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