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)

Peptide phage display libraries were screened for peptides that bind to the tumour suppressor protein, human p53. Three p53 binding peptides were isolated respectively from hexamer (6-mer), dodecamer (12-mer) and icosomer (20-mer) libraries. We have characterised their interaction with p53 in detail. The phage appear to bind regions on native p53 common between mouse and man. Two conformation-specific anti-p53 monoclonal antibodies were used to dissect the phage-p53 interaction, the phage were found to preferentially bind the PAb1620-p53 conformation rather than the PAb240-p53 conformation. Mapping experiments indicated the C-terminal 30 amino acid residues of p53 were dispensable for phage binding and that the binding of SV40 large T-antigen and the phage were not mutually exclusive. Interestingly the phage were seen to exhibit differential binding to wild-type human p53 over the two point mutant p53 proteins, His175 and Trp248. Ultimately the phage appear to selectively target native wild-type p53, mimicking the specificity of SV40 large T-antigen. The ability to target specific sub-populations of p53 could be an important step in the development of therapeutics for the treatment of p53-based human malignancy.
J Mol Biol 1994 Nov 04
PMID:The characterisation of p53 binding phage isolated from phage peptide display libraries. 796 88

Vestibular schwannoma occurs both as a sporadic tumour and in the dominantly inherited familial cancer syndrome neurofibromatosis type 2 (NF2). The gene for NF2 has recently been isolated on chromosome 22, and the demonstration of inactivating germline mutations in NF2 patients and NF2 associated tumours suggests that it act as a tumour suppressor. We have investigated 85 sporadic and 2 NF2 associated vestibular schwannomas, and one vagal schwannoma for chromosome 22 allele loss and NF2 gene mutations. A further 7 vestibular schwannomas were investigated for NF2 mutations only. Chromosome 22 allele loss was detected in 34 of 87 vestibular schwannomas and in the vagal nerve schwannoma. Six exons of the NF2 gene were investigated by SSCP analysis in all 95 tumours. Somatic NF2 gene mutations were detected in 13 non-familial vestibular schwannomas and in one of the NF2 vestibular schwannomas. Seven non-familial tumours with an NF2 gene mutation also displayed a chromosome 22 allele loss. Thirteen of the mutations were predicted to produce truncation of the NF2 protein. These results suggest that somatic mutations of the NF2 tumour suppressor gene are a critical step in the pathogenesis of both familial and non-familial vestibular schwannoma and that the mechanism of tumourigenesis complies with a 'two-hit' mutation model.
Hum Mol Genet 1994 Feb
PMID:Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma. 800 7

The adenomatous polyposis coli (APC) gene, which transmits familial adenomatous polyposis, is frequently mutated in sporadic colorectal tumours. Acquired somatic mutations have also been reported in a second gene, mutated in colorectal cancer (MCC), which lies within 500 kb of APC on chromosome 5q21 and has thus been implicated in tumour development. Further evidence for an oncosuppressor gene other than APC on chromosome 5q comes from recent studies of lung, renal and hepatic cancers in which there is loss of heterozygosity of 5q21 but no somatic APC mutations. To investigate the relative importance of APC and MCC in sporadic colorectal cancer, we have assessed the extent of 5q21 allelic loss in 80 carcinomas. All informative tumours exhibiting allelic loss had deletions which included both APC and MCC. In 21 tumours with loss of heterozygosity in MCC we have screened the entire coding region of the gene for mutation of the retained allele and found no evidence for mutation. The data indicate that independent loss of MCC is a rare event, and that in cases where allele loss occurs mutation of the retained allele is uncommon. This suggests that MCC does not function as an independent tumour suppressor in the majority of colorectal cancers.
Hum Mol Genet 1994 Mar
PMID:Loss of heterozygosity of MCC is not associated with mutation of the retained allele in sporadic colorectal cancer. 801 55

The recent identification of the NF2 tumour suppressor gene has enabled large scale screening for pathological mutations in the gene. We have sought germline mutations in the NF2 gene by SSCP and heteroduplex analysis of cDNA and genomic DNA samples followed by cloning and sequencing of mutant alleles. In the present report we describe 11 putative pathological mutations, including five nonsense mutations, three short insertions or deletions causing frameshifts and three missense mutations. Most stop mutations and frameshift mutations were found in individuals expressing a severe phenotype while one of the three missense mutations was associated with a mild phenotype. Four unrelated NF2 patients of the 93 tested were found to have identical nonsense mutations caused by a C to T transition (C169) in a CpG dinucleotide, which is a potential mutational hotspot in the NF2 tumour suppressor gene.
Hum Mol Genet 1994 May
PMID:Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. 808 68

The FAU gene (FBR-MuSV associated ubiquitously expressed gene) encodes the ribosomal protein S30 fused with a Ubiquitin-like molecule. The FAU gene is expressed in a wide range of tissues, is evolutionarily conserved, and has putative tumour suppressor activity in vitro. The human FAU gene maps to the long arm of chromosome 11 band q13, close to the PYGM locus. This locus is tightly linked to the Multiple Endocrine Neoplasia type 1 (MEN1) locus. The FAU gene properties, together with its chromosomal localisation on 11q13, make it a candidate gene for MEN1. To test this hypothesis we screened 33 unrelated patients with MEN1 for constitutional genetic alterations in the FAU gene by Southern blot analysis, denaturing gradient gel electrophoresis (DGGE) and in two cases complemented by DNA sequencing to confirm the DGGE data. Furthermore, 10 parathyroid and pancreatic tumours from MEN1 patients and 15 each of sporadic parathyroid and pituitary tumours were similarly examined. In addition, we studied the expression of the FAU gene at the RNA level in 9 MEN1-associated tumours by Northern blot analysis. No FAU gene anomalies could be demonstrated by any of these techniques. We conclude that FAU is not likely to be the MEN1 tumour suppressor gene.
Hum Mol Genet 1993 Apr
PMID:Exclusion of FAU as the multiple endocrine neoplasia type 1 (MEN1) gene. 809 2

We have analyzed a single multi-affected breast/ovarian cancer pedigree (BOV3) and have shown consistent inheritance of markers on chromosome 17q with the disease confirming that this family is due to the BRCA1 gene. Analysis of 17q haplotypes shows a recombination event in a bilateral breast cancer case which suggests that the BRCA1 gene lies distal to D17S857; D17S857 is thus the new proximal boundary for the region containing BRCA1. Combining this information with previously published mapping information suggests that BRCA1 is contained in a region estimated at 1-1.5 Mb in length. All seven breast tumour/blood pairs examined from this family show loss of heterozygosity in the tumours. The allel retained in each tumour was from the disease-bearing chromosome implicating BRCA1 as a tumour suppressor gene. We have sequenced the 17 beta-oestradiol dehydrogenase genes (EDH17B1 and EDH17B2) which have been suggested as candidate genes for BRCA1 in four members of this family. No germline mutations were detected.
Hum Mol Genet 1993 Nov
PMID:Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1. 828 Nov 42

Quaternary interactions of p53 influence its tertiary structure which, in turn, is critical for sequence-specific DNA binding and tumour suppressor function. Given its regulatory potential we have sought to define the quaternary structure of p53 involved in sequence-specific DNA binding. Double stranded DNA [5'-GGACATGCCCGGGCATGTCC-3'; Funk et al. (1992) Mol. Cell. Biol., 12, 2866-2871] was used to test p53 binding capacity in vitro. The p53 protein was translated in vitro and size fractionated prior to the DNA binding reaction. Two independent DNA binding assays were employed. The first detected electromobility shift of 32P-labelled DNA and was carried out in the presence of PAb421, which stabilises and supershifts p53-DNA complexes. The second detected 35S-labelled p53 bound to biotinylated target DNA in the absence of PAb421. Sequence-specific DNA binding was found to be a property of full length, oligomeric p53. Greatest binding activity involved tetramers and/or higher molecular weight forms of p53, minimal binding was observed for dimers. This size profile was unaffected by PAb421 and it therefore seems unlikely that PAb421 dissociates high molecular weight forms of p53 into dimers. We conclude that high molecular weight forms of p53 are the most effective structures for sequence-specific DNA binding in vitro; these structures may represent tetramers and/or heterogeneous complexes of p53 with other proteins.
 ...
PMID:Analysis of p53 quaternary structure in relation to sequence-specific DNA binding. 830 93

The p16 gene has been identified as a candidate tumour suppressor gene at 9p21, a region commonly deleted in bladder cancer. We screened 140 bladder tumours and 16 cell lines for deletions and sequence variants of p16. Eight cell lines showed homozygous deletion of p16 and two had small sequence variations. All 13 tumours with small defined deletions of 9p21, 18/31 (58%) of tumours with monosomy 9 and 9/91 (10%) of tumours with no chromosome 9 loss of heterozygosity had homozygous deletion of p16. No tumour-specific sequence variants were identified. Deletion mapping revealed a nested set of deletions focused on p16. Six deletions involved p16 but not the related and adjacent gene p15 and one tumour had an intragenic deletion of p16. All other deletions involved both p16 and p15. We conclude that p16 represents the major target for deletion at 9p21 in bladder cancer.
Hum Mol Genet 1995 Sep
PMID:p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. 854 41

The chromosome region 17p13.3 is thought to encode a tumour suppressor gene involved in sporadic breast cancer and other malignancies. Physical ordering of markers has been carried out by a series of multicolour fluorescent in situ hybridisation (FISH) experiments, using isolated yeast artificial chromosomes (YACs) and cosmids. Eight polymorphic markers ordered within this new physical map and one external marker were used to investigate the pattern of loss of heterozygosity in a panel of 40 sporadic breast tumour patients. The data revealed a region of high loss (60%) within distal 17p13.3, defined by markers D17S926, D17S695 and D17S849 which mapped close together. A contig of YACs was constructed physically linking these three markers.
Hum Mol Genet 1995 Nov
PMID:Detailed mapping and loss of heterozygosity analysis suggests a suppressor locus involved in sporadic breast cancer within a distal region of chromosome band 17p13.3. 858 80

Germ-line mutations of the TSC2 tumour suppressor gene have been identified in humans with tuberous sclerosis and in the Eker rat. Tuberin, the human TSC2 gene product, has a small region of homology with rap1GAP and stimulates rap1 GTPase activity in vitro, suggesting that one of its cellular roles is to function as a GTPase activating protein (GAP). We have undertaken a comparative analysis of the TSC2 gene in human and the pufferfish, Fugu rubripes. In addition to the GAP domain, three other regions of the proteins are highly conserved (peptide sequence similarity > 80%). These regions are likely to represent further functional domains. To facilitate analysis of mutations within these domains we have determined the genomic structure of the human TSC2 gene. It comprises 41 exons, including exon 31 which was absent from the originally described spliceoform of the human TSC2 transcript and was identified following exon prediction from Fugu genomic sequence. These findings support the proposal of the Fugu genome as a tool for human gene analysis.
Hum Mol Genet 1996 Jan
PMID:Comparative analysis and genomic structure of the tuberous sclerosis 2 (TSC2) gene in human and pufferfish. 884 53


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