Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of oral and head and neck squamous cell carcinomas occurs in relation with multiple events including mainly: loss of cycle cell control, evasion from apoptosis, telomerase reactivation. Complex interactions between a set of molecules, cell cycle proteins, tumour suppressor genes, oncogenes and the telomerase, occur in the multiple step process of carcinogenesis. The 2 main ways of control of the cell cycle rely on 2 tumour suppressor genes: the P53 gene and the retinoblastoma gene or RB gene. One of the regulation pathways or the 2 regulation pathways are disabled during the development of oral and head and neck squamous cell carcinomas. Most of the time, the inactivation of the P53 pathway results from a loss of function of the p53 protein, secondary to mutation and/or deletion of the P53 gene; It may also result of the amplification of the MDM2 gene and of the inactivation of the arf protein. The RB pathway leads to cell proliferation by loss of the p16 protein, by amplification of the cyclin D1 gene and less frequently by mutation of the RB gene or loss of the retinoblastoma protein. In India and South-East Asia, the activation of RAS and MYC oncogenes appears to be related with the presence of specific carcinogens in snuff and tobacco. By blocking apoptosis, the Bcl2 protein seems to increase the resistance of tumours to radiotherapy and chemotherapy.
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PMID:[Genic alterations in oral and head and neck squamous cell carcinomas: analysis of international literature]. 1278

In sarcomas, the TP53 tumour suppressor pathway may be altered either by TP53 mutations or by amplification of MDM2, encoding a protein that inhibits TP53 and targets it for 26S-proteasome degradation. However, in the majority of the analysed clinical samples, neither of these types of aberrations are found, suggesting that additional mechanisms are involved. The present study shows that COPS3, located in 17p11 and encoding a component of the proteasome pathway, is more frequently amplified in osteosarcomas (OS) than is MDM2. We present detailed analysis of TP53 mutations and MDM2 and COPS3 expression levels in a set of 23 OS. Our results show that none of the tumours with COPS3 amplification had MDM2 amplification nor TP53 mutations, consistent with the hypothesis that one of the three aberrations is sufficient. The results suggest that inactivation of otherwise intact TP53 by aberrations in the proteasome pathway may contribute to the characteristic aneuploidy observed in OS.
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PMID:Amplification and overexpression of COPS3 in osteosarcomas potentially target TP53 for proteasome-mediated degradation. 1291 37

The transcriptional co-activator CBP [CREB (cAMP-response-element-binding protein)-binding protein] and its paralogue p300 play a key role in the regulation of both activity and stability of the tumour suppressor p53. Degradation of p53 is mediated by the ubiquitin ligase MDM2 (mouse double minute protein) and is also reported to be regulated by CBP/p300. Direct protein-protein interaction between a central domain of MDM2 and the TAZ1 (transcriptional adaptor zinc-binding domain) [C/H1 (cysteine/histidine-rich region 1)] domain of p300 and subsequent formation of a ternary complex including p53 have been reported previously. We expressed and purified the proposed binding domains of HDM2 (human homologue of MDM2) and CBP, and examined their interactions using CD spectroscopy. The binding studies were extended by using natively purified GST (glutathione S-transferase)-p300 TAZ1 and GST-p53 fusion proteins, together with in vitro translated HDM2 fragments, under similar solution conditions to those in previous studies, but omitting added EDTA, which causes unfolding and aggregation of the zinc-binding TAZ1 domain. Comparing the binding properties of the known TAZ1 interaction partners HIF-1alpha (hypoxia-inducible factor 1), CITED2 (CBP/p300-interacting transactivator with glutamic- and aspartic-rich tail) and STAT2 (signal transducer and activator of transcription 2) with HDM2, our data suggest that TAZ1 in its native state does not serve as a specific recognition domain of HDM2. Rather, unfolded TAZ1 and HDM2 proteins have a high tendency to aggregate, and non-specific protein complexes are formed under certain conditions.
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PMID:The CBP/p300 TAZ1 domain in its native state is not a binding partner of MDM2. 1527 Jul

The p53 tumour suppressor protein is a highly potent transcription factor which, under normal circumstances, is maintained at low levels through the action of MDM2, an E3 ubiquitin ligase which directs p53 ubiquitylation and degradation. Expression of the mdm2 gene is stimulated by p53 and this reciprocal relationship forms the basis of a negative feedback loop. Both genotoxic and non-genotoxic stresses that induce p53 focus principally on interruption of the p53-MDM2 loop with the consequence that p53 becomes stabilised, leading to changes in the expression of p53-responsive genes. The biological outcome of inducing this pathway can be either growth arrest or apoptosis: factors affecting the functioning of the loop, the biochemical activity of p53 itself and the cellular environment govern the choice between these outcomes in a cell type- and stress-specific manner.
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PMID:The p53 response to DNA damage. 1527 92

The MDM2 proto-oncogene, which encodes a protein that binds to the p53 tumour suppressor, has been found amplified and overexpressed in a range of human tumours. Although the human MDM2 cDNA sequence has been reported, the genomic organisation of the human gene has not been documented. We have previously reported the detection of five alternative internally deleted MDM2 transcripts in human tumours and suggested these may represent alternatively spliced forms. Here we demonstrate two novel MDM2 transcripts with internal deletions, using RT-PCR followed by sequencing. To definitively ascribe these variant transcript forms to alternative splicing, and to explore associated mechanisms, we have determined the intron--exon organisation of the human genomic sequence. The human MDM2 gene spans approximately 33 kb and is divided into 12 exons. Exon sizes range from 50 to > or =1161 bp and intron sizes vary from 121 to approximately 7000 bp. The positions of intron--exon boundaries are compared with the deletion junctions of the multiple-sized transcripts and discussed in relation to alternative splicing mechanism.
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PMID:Genomic organisation of the human MDM2 oncogene and relationship to its alternatively spliced mRNAs. 1531 25

The tumour suppressor p53 is a transcription factor with powerful antitumour activity that is controlled by its negative regulator MDM2 (mouse double minute 2, also termed HDM2 in humans) through a feedback mechanism. MDM2, which is overproduced in many tumours, binds p53 and inhibits its function by modulating its transcriptional activity and stability. Activation of p53 in tumour cells by inhibiting its physical interaction with MDM2 has been in the focus of cancer drug discovery. However, development of nonpeptidic MDM2 antagonists turned out to be challenging. Recently, the first potent and selective small-molecule antagonists of MDM2, the Nutlins, have been identified. Studies with Nutlins provided in vitro and in vivo proof-of-principle for targeting p53-MDM2 interaction for cancer therapy.
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PMID:Targeting the p53-MDM2 interaction to treat cancer. 1545 48

As combinations of genetic and/or epigenetic alterations occurring during salivary gland carcinogenesis are largely unknown, we here analyzed 36 salivary gland carcinomas (SGCs) for changes in INK4a/ARF, RB1, p21, p27, PTEN, p53, MDM2 and O6-MGMT genes using methylation specific PCR (MSP), loss of heterozygosity (LOH) assays and mutational analysis with immunohistochemistry (IHC), as well as histone H3 and H4 acetylation status. The RB1 gene was found to be the most frequently methylated (41.7% of cases), while methylation of p27(Kip1) and O6-MGMT were less frequent 8.3% and 5.6%, respectively). Two other genes, p21(Waf1) and PTEN, were unmethylated in the SGCs examined. RB1 methylation significantly correlated with loss of expression as determined by IHC (P=0.03), and also a poor prognosis (P=0.02). p53 mutations were found in 8 cases (22.2%), coupled with p14ARF hypermethylation in two cases. LOH in INK4a/ARF and the RB1 locus was observed in 33.3% and 28.6% of the lesions, respectively. There was no correlation between 9p21 LOH and methylation of the INK4a/ARF gene. Promoter hypermethylation of RB1 coupled with LOH was evident in three samples immuno-negative for RB1. Acetylation of histone H3 and H4 was detected in 6 and 5 cases, respectively. These findings indicate that epigenetic silencing of tumour suppressor genes via promoter hypermethylation might be crucial for salivary gland carcinogenesis, particularly in the RB1 gene. Thus epigenetic events including methylation and acetylation as well as genetic alterations may have important contributions.
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PMID:Genetic and epigenetic alteration profiles for multiple genes in salivary gland carcinomas. 1569 18

Critical to the inhibitory action of the oncogene product, MDM2, on the tumour suppressor, p53, is association of the N-terminal domain of MDM2 (MDM2N) with the transactivation domain of p53. The structure of MDM2N was previously solved with a p53-derived peptide, or small-molecule ligands, occupying its binding cleft, but no structure of the non-liganded MDM2N (i.e. the apo-form) has been reported. Here, we describe the solution structure and dynamics of apo-MDM2N and thus reveal the nature of the conformational changes in MDM2N that accompany binding of p53. The new structure suggests that p53 effects displacement of an N-terminal segment of apo-MDM2N that occludes access to the shallow end of the p53-binding cleft. MDM2N must also undergo an expansion upon binding, achieved through a rearrangement of its two pseudosymetrically related sub-domains resulting in outward displacements of the secondary structural elements that comprise the walls and floor of the p53-binding cleft. MDM2N becomes more rigid and stable upon binding p53. Conformational plasticity of the binding cleft of apo-MDM2N could allow the parent protein to bind specifically to several different partners, although, to date, all the known liganded structures of MDM2N are highly similar to one another. The results indicate that the more open conformation of the binding cleft of MDM2N observed in structures of complexes with small molecules and peptides is a more suitable one for ligand discovery and optimisation.
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PMID:Structure of free MDM2 N-terminal domain reveals conformational adjustments that accompany p53-binding. 1595 16

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14(ARF)and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P=0.009). This association was consistent in multivariate analysis, including adjustment for age (P=0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy.
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PMID:Mutations in Rb1 pathway-related genes are associated with poor prognosis in anaplastic astrocytomas. 1597 Sep 25

Mutation and/or loss of the TP53 tumour suppressor gene is the single most common genetic abnormality in human cancer. The majority of TP53 mutations lead to stabilization of the protein, so that immunohistochemical staining for p53 can suggest mutation status in many cases. However, various false-positive and false-negative situations mean that simple immunostaining for p53 is not informative in a substantial number of tumours. In the present study, a series of 119 human cancers were immunostained using a highly sensitive technique that detects the low levels of wild-type protein expressed in normal cells, such that homozygous gene deletion or non-sense TP53 mutation can be identified by an absence of staining. TP53 gene status was also assessed using FASAY as a genetic/functional screen and in selected cases by direct sequencing. A quantitative scoring system was employed to assess p53 levels, and p53 post-translational modification was evaluated using antibodies that detect specific phosphorylation sites. Phosphorylated p53 correlated with total p53 levels and did not improve the prediction of TP53 mutation status. The transcriptional activity of TP53 was determined by staining for two downstream target genes, p21(WAF1) and MDM2, and statistical correlations between MDM2/p21(WAF1) and p53 were found in tumours with wild-type, but not mutant TP53. Measurement of staining for p53 and MDM2 accurately identifies the TP53 status of tumours. This simple and cost-effective method, applicable to automated staining and quantitation methods, improves the identification of TP53 status over standard methods for p53 immunostaining and provides information about tumour p53 phenotype that is complementary to genotyping data.
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PMID:Discriminating functional and non-functional p53 in human tumours by p53 and MDM2 immunohistochemistry. 1616 Oct 5


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