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

The breast cancer specific tumour suppressor protein, BRCA1 (refs 1,2), activates transcription when linked with a DNA-binding domain and is a component of the RNA polymerase II (Pol II) holoenzyme. We show here that RNA helicase A (RHA) protein links BRCA1 to the holoenzyme complex. The region of BRCA1 which interacts with RHA and, thus, the holoenzyme complex, corresponds to subregions of the BRCT domain of BRCA1 (ref. 9). This interaction was shown to occur in yeast nuclei, and expression in human cells of a truncated RHA molecule which retains binding to BRCA1 inhibited transcriptional activation mediated by the BRCA1 carboxy terminus. These data are the first to identify a specific protein interaction with the BRCA1 C-terminal domain and are consistent with the model that BRCA1 functions as a transcriptional coactivator.
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PMID:BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. 966 97

The tumour suppressor protein p53 is a stress-activated transcription factor whose activity is required for regulating the cellular response to stress and damage. The biochemical activity of p53 as a transcription factor can be regulated by partner proteins affecting stability, nuclear transport, signalling pathways modulating phosphorylation and interactions with components of the transcriptional machinery. The key structural determinants of p53 protein that drive sequence-specific DNA binding include the core specific DNA-binding domain and the tetramerization domain. Flanking these domains are more evolutionarily divergent carboxy- and amino-terminal regulatory motifs that further modulate tetramerization and sequence-specific transactivation. This review will mainly focus on the mechanisms whereby the tetramerization domain modulates sequence-specific DNA binding and how missense point mutations in p53 protein and the activity of molecular chaperones may lead to unfolding of mutant p53 tetramers in human tumours.
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PMID:Regulation of p53 protein function through alterations in protein-folding pathways. 1006 54

The p53 gene is a tumour suppressor gene which has a fundamental role in cell cycle control and division, and in mammals certain genotoxic agents induce specific mutations in p53, leading to tumourigenesis. Fish have been investigated as models for studying carcinogens, but as yet very little data exists that links exposure to specific chemicals with the aetiology of tumours found in wild populations. In this study, p53 was sequenced from five species of fish with a view to the possible use of mutations in the highly conserved domains of p53 to identify genotoxins in the aquatic environment. A 0.8 kb fragment of the cDNA encompassing the conserved DNA-binding domain of p53 was sequenced in three Oncorhynchus salmonid fish: coho (O. kisutch), chum (O. keta), and chinook (O. tshawytscha) and full-length p53 cDNAs were sequenced in the puffer fish (Tetraodon miurus) and the barbel (Barbus barbus). The full-length puffer fish and barbel p53 cDNAs were 1834 bp and 1790 bp in length, encoding a 367 aa protein and a 369 aa protein, respectively. The deduced aa sequences of the p53 cDNA in the Oncorhynchus salmon shared a 100% identity in the five conserved regions (I-V). Comparisons of the deduced aa sequences for puffer fish and barbel p53 with other fish p53s revealed a high homology within the conserved DNA binding domain (68-86% for puffer fish and between 66-88% for barbel). "Conserved" domain I was not highly conserved in fish, as it is in mammals, and, therefore, conserved domains II-V are most likely to provide the valuable sequences in fish p53 for use in mutational studies to fingerprint genotoxins in the aquatic environment.
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PMID:Fish p53 as a possible biomarker for genotoxins in the aquatic environment. 1033 19

Chromosomal translocations resulting in the expression of chimaeric transcription factors are frequently observed in tumour cells, and have been suggested to be a common mechanism in human carcinogenesis. Ewing sarcoma and related peripheral primitive neuroectodermal tumours share recurrent translocations that fuse the gene EWSR1 (formerly EWS) from 22q-12 to FLI1 and genes encoding other ETS transcription factors (which bind DNA through the conserved ETS domain). It has been shown that transduction of the gene EWSR1-FLI1 (encoding EWS-FLI1 protein) can transform NIH3T3 cells, and that mutants containing a deletion in either the EWS domain or the DNA-binding domain in FLI1 lose this ability. This indicates that the EWS-FLI1 fusion protein may act as an aberrant transcription factor, but the exact mechanism of oncogenesis remains unknown. Because ETS transcription factors regulate expression of TGFBR2 (encoding the TGF-beta type II receptor, TGF-beta RII; Refs 9,14), a putative tumour suppressor gene, we hypothesized that TGFBR2 may be a target of the EWS-FLI1 fusion protein. We show here that Ewing sarcoma [corrected] (ES) cell lines with the EWSR1-FLI1 fusion have reduced TGF-beta sensitivity, and that fusion-positive ES cells and primary tumours both express low or undetectable levels of TGFBR2 mRNA and protein product. Co-transfection of FLI1 and the TGFBR2 promoter induces promoter activity, whereas EWSR1-FLI1 leads to suppression of TGFBR2 promoter activity and FLI1-induced promoter activity. Introduction of EWSR1-FLI1 into cells lacking the EWSR1-FLI1 fusion suppresses TGF-beta RII expression, whereas antisense to EWSR1-FLI1 in ES cell lines positive for this gene fusion restores TGF-beta RII expression. Furthermore, introduction of normal TGF-beta RII into ES cell lines restores TGF-beta sensitivity and blocks tumorigenicity. Our results implicate TGF-beta RII as a direct target of EWS-FLI1.
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PMID:Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. 1050 22

The p53 tumour suppressor protein exerts multiple, antiproliferative effects in response to genotoxic exposures. Reactive oxygen intermediates (ROI) play several distinct roles in the p53 pathway. First, they are important activators of p53 through their capacity to induce DNA strand breaks. Second, they regulate the DNA-binding activity of p53 by modulating the redox status of a critical set of cysteines in the DNA-binding domain, which are also involved in the coordination of zinc. Third, they play a role in the signalling pathways regulated by p53, as several genes encoding redox effectors are transcriptionally controlled by p53. In this review, we summarize the evidence for the involvement of ROI at these three levels. Emphasis is placed on the role of metals and ROI as potential regulators of p53 protein conformation and functions, and on the putative toxicological consequences of such a regulation.
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PMID:Redox signalling and transition metals in the control of the p53 pathway. 1060 31

The tumour suppressor gene p53 is extensively studied for its importance in cancer. In its active conformation, p53 is tetrameric and one domain - the tetramerization domain - permits the oligomerization of this protein. Until recently, little attention was given to this domain because, in contrast to the DNA-binding domain, it is not often mutated in cancer. However, various experimental studies have shown evidence that the tetramerization domain is essential for DNA binding, protein-protein interactions, post-translational modifications, and p53 degradation. Moreover, single mutations in the tetramerization domain can inactivate the wild-type protein in a manner similar to that seen with mutations in the DNA-binding domain. Interestingly, the phenotype of several tetramerization domain mutants differs from that observed with DNA-binding domain mutants. In this review, current knowledge about the importance of the tetramerization domain to the function of p53 will be summarized.
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PMID:The role of tetramerization in p53 function. 1142 Jun 72

The induction of anti-DNA autoantibodies in systemic lupus erythematosus (SLE) patients is problematic because mammalian DNA is poorly immunogenic at best. Here we demonstrate a chain of connected antibodies in SLE patient sera that could account for the induction of anti-DNA antibody, and possibly for some of the pathogenic features of SLE. We now report that SLE patients, in addition to anti-DNA, produce antibodies to the carboxy-terminal domain of the tumour suppressor molecule p53; this p53 domain recognizes damaged DNA. Hence, these anti-p53 antibodies could mimic damaged DNA immunologically. Indeed, SLE sera do contain anti-idiotypic antibodies to a prototypic anti-p53 antibody. Moreover, SLE anti-DNA antibodies also recognize this type of anti-p53 antibody. Indeed, binding of affinity-purified anti-DNA both to DNA and to the anti-p53 antibody could be blocked by a p53 peptide derived from the DNA-binding domain. This mimicry of the p53 DNA-binding domain by the SLE anti-DNA antibodies is functional: activation of the p53 molecule could be inhibited by such anti-DNA antibodies. Thus, anti-DNA antibodies may arise in SLE patients by a chain of idiotypic autoimmunity centered around p53 autoimmunity. The SLE anti-DNA and anti-p53 antibodies can functionally block p53 activation, and so could affect apoptosis.
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PMID:Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies. 1148 38

The BRCT (BRCA1 C-terminus) is an evolutionary conserved protein-protein interacting module found as single, tandem or multiple repeats in a diverse range of proteins known to play roles in the DNA-damage response. The BRCT domains of 53BP1 bind to the tumour suppressor p53. To investigate the nature of this interaction, we have determined the crystal structure of the 53BP1 BRCT tandem repeat in complex with the DNA-binding domain of p53. The structure of the 53BP1-p53 complex shows that the BRCT tandem repeats pack together through a conserved interface that also involves the inter-domain linker. A comparison of the structure of the BRCT region of 53BP1 with the BRCA1 BRCT tandem repeat reveals that the interdomain interface and linker regions are remarkably well conserved. 53BP1 binds to p53 through contacts with the N-terminal BRCT repeat and the inter-BRCT linker. The p53 residues involved in this binding are mutated in cancer and are also important for DNA binding. We propose that BRCT domains bind to cellular target proteins through a conserved structural element termed the 'BRCT recognition motif'.
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PMID:Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor. 1211 May 97

A complex of the DNA-binding domain of the tumour suppressor p53 bound to the BRCT domains of the p53-binding protein (53BP1) has been prepared and purified. Single crystals have been obtained using the microbatch technique with polyethylene glycol 4 kDa and ammonium sulfate. Crystals diffract X-rays to beyond 2.3 A and belong to the space group P2(1)2(1)2(1). Several complete data sets have been collected from a number of crystals, each with different unit-cell parameters. Partial structures have been produced by successful placement of two copies of the p53 core region into the asymmetric unit. There is clear evidence for the binding protein and a complete structure determination is under way.
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PMID:Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor. 1235 27

Alterations in tumour suppressor p53 gene are the most common defects seen in a variety of human cancers. In order to study the significance of the p53 gene in the genesis and development of human glioma from Indian patients, we checked 44 untreated primary gliomas for mutations in exons 5-9 of the p53 gene by PCR-SSCP and DNA sequencing. Sequencing analysis revealed six missense mutations. The incidence of p53 mutations was 13.6% (6 of 44). All the six mutations were found to be located in the central core domain of p53, which carries the sequence-specific DNA-binding domain. These results suggest a rather low incidence but a definite involvement of p53 mutations in the gliomas of Indian patients.
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PMID:Alterations in tumour suppressor gene p53 in human gliomas from Indian patients. 1257 72


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