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 p53 gene has been implicated as a tumour suppressor, with mutations occurring in many carcinomas, such as colon, breast and lung. We have sequenced exons 5, 7 and 8 containing conserved gene regions in the only available differentiated thyroid follicular carcinoma cell line and found a mutation at position 273, Arg----His, with no normal allele present. The same mutation was also present in DNA from the tumour of origin. However immunohistochemical analysis of 129 human thyroid tumours using a panel of p53 antibodies was unequivocally negative. Southern blotting in 20 cases failed to demonstrate any deletion or rearrangement, and direct genomic sequencing of 20 carcinomas showed normal DNA sequence for exons 5, 7 and 8. Thus p53 abnormalities may not be important in human thyroid carcinogenesis, in contrast to colon, breast and lung. However, the FTC 133 cell line was only established after 132 unsuccessful attempts with other differentiated thyroid follicular tumours. Since this line and the corresponding tumour of origin have a p53 mutation, we propose that p53 mutation may confer on thyroid follicular tumour cells the ability to grow in culture. This has potential applications for the future development of thyroid carcinoma cell lines.
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PMID:Mutation of the p53 gene in a differentiated human thyroid carcinoma cell line, but not in primary thyroid tumours. 192 34

Denys-Drash syndrome (DDS) is characterized by early onset nephropathy, pseudohermaphroditism in males and a high risk for developing Wilm's tumour (WT). The exact cause of DDS is unknown but germline mutations in the Wilm's tumour suppressor gene (WT1) have recently been described in the majority of DDS patients studied. These mutations occur de novo and are clustered around the zinc finger (ZF) coding exons of the WT1 gene. Analysis of exons 2-10 of the WT1 gene in constitutional DNA from five patients with DDS was carried out using the polymerase chain reaction (PCR) and direct DNA sequencing. In four out of the five patients, heterozygous germline mutations were found: a novel point mutation in exon 8 (ZF2) at codon 377 altering the wild-type histidine to arginine, and three previously described point mutations in exon 9 (ZF3) in the codons corresponding to amino acids 394Arg and 396Asp. In one patient, no mutations could be demonstrated. In three patients where parental DNA was available, the mutations were shown to have occurred de novo. Furthermore, since tumour DNA in two of these cases had lost the wild-type allele, polymorphic markers from the short arm of chromosome 11 were used to determine the parental origin of the mutant chromosome. In both cases, the mutant chromosome was shown to be of paternal origin. Since the majority of published WT1 mutations in DDS patients alter a RsrII restriction site in exon 9, we were able to perform PCR-based diagnosis in a female patient with early renal insufficiency and normal external genitalia.
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PMID:WT1 mutations in patients with Denys-Drash syndrome: a novel mutation in exon 8 and paternal allele origin. 811 32

p53 tumour suppressor gene mutations were studied in 118 renal cell carcinomas using paraffin-embedded surgical material. Optimal results were obtained with analysis of exon lengths between 150 and 200 base pairs for polymerase chain reaction. Single strand conformation polymorphism and sequencing analysis revealed only two point mutations (2/118, 2%): one involving codon 135; TGC-->TTC (cysteine-->phenylalanine) and the other codon 175; CGC-->CAC (arginine-->histidine). Both of these cases were classified as granular cell subtype on microscopic observation. The data suggest that the p53 tumour suppressor gene is not related to tumour initiation, promotion, or progression of renal cell carcinomas. However, there is the possibility that granular cell type carcinomas may have a different genetic background from clear cell type renal neoplasms.
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PMID:Polymerase chain reaction-single strand conformation polymorphism analysis of the p53 gene in paraffin-embedded surgical material from human renal cell carcinomas. 818 88

Aberrations of the p53 and Rb tumour suppressor genes were examined in 12 human hepatocellular carcinoma (HCC)-derived cell lines from different geographic areas and 9 local HCCs by restriction fragment length polymorphisms (RFLP), polymerase chain reaction-single-strand conformation polymorphisms (PCR-SSCP) and DNA sequencing. The relationships between genetic changes and hepatitis B virus (HBV) DNA integration in samples were compared. None of the cell lines and tumours showed structural changes in the Rb gene, while 6 cell lines and 2 tumours had mutation or deletion in exons 5 to 8 of p53. Mutations include an AGG --> AGT (Arg --> Ser) transversion at codon 249 in PLC/PRF/5 and Mahlavu, an AAT --> AAA (Asn --> Cys) transversion at codon 200 in TONG/HCC, an AAG --> GAG (Lys --> Glu) transition at codon 139 in HCC-T, a CAT --> CGT (His --> Arg) transition at codon 214 in SC4, and a CCC --> CTC (Pro --> Leu) transition at codon 250 in SC8. In Huh4, an 18-bp deletion from codon 264 to 270 resulted in loss of Leu-Gly-Arg-Asn-Ser-Phe from the amino acid sequences 265 to 270, whereas Hep3B had a 7-kb deletion after exon 7 of p53. Our data indicate that whereas Rb may not have pleiotropic effects on HCC, p53 aberrations are frequently involved in hepatocarcinogenesis. Further, HBV infection appears to be unrelated to the micro-genetic changes of p53. The G to T codon-249-mutation is consistent with HCCs arising from areas at high risk for both aflatoxin B1 (AFB1) exposure and HBV infection.
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PMID:Tumour suppressor p53 and Rb genes in human hepatocellular carcinoma. 877 41

Histidine triad nucleotide-binding protein (HINT), a dimeric purine nucleotide-binding protein from rabbit heart, is a member of the HIT (histidine triad) superfamily which includes HINT homologues and FHIT (HIT protein encoded at the chromosome 3 fragile site) homologues. Crystal structures of HINT-nucleotide complexes demonstrate that the most conserved residues in the superfamily mediate nucleotide binding and that the HIT motif forms part of the phosphate binding loop. Galactose-1-phosphate uridylyltransferase, whose deficiency causes galactosemia, contains tandem HINT domains with the same fold and mode of nucleotide binding as HINT despite having no overall sequence similarity. Features of FHIT, a diadenosine polyphosphate hydrolase and candidate tumour suppressor, are predicted from HINT-nucleotide structures.
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PMID:Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins. 916 65

A probable diagnosis of von Hippel-Lindau disease was made in a two generation family in which the proband had a phaeochromocytoma, renal cysts, and multiple cerebral cavernomas. His sister had multiple similar cerebral vascular lesions and his father died from renal carcinoma aged 42. Although the family did not satisfy the conventional diagnostic criteria for von Hippel-Lindau disease, an underlying germline mutation in the von Hippel-Lindau disease tumour suppressor gene was identified in the proband. Molecular genetic analysis not only confirmed the putative diagnosis of the disease in the proband but also showed that the cerebral vascular lesions segregated independently from the von Hippel-Lindau disease mutation. This report exemplifies how molecular genetic investigations can enhance the diagnosis and management of families with suspected von Hippel-Lindau disease, particularly when the manifestations, as in this family, are not typical.
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PMID:Independent segregation of von Hippel-Lindau disease and cerebral cavernomas. 940 11

Exons 4 to 8 of the tumour suppressor gene p53 were analysed in 25 skin and 25 mammary tumours of 50 dogs. A 1 bp deletion (ACC-->AC) was detected in codon 89 in exon 4 in a squamous cell carcinoma. A missense mutation CGC-->CAC (arginine-->histidine) was present in codon 162 in exon 5 in a mammary adenocarcinoma. Moreover, a silent mutation occurred in codon 103 (serine) of exon 4 in a mammary adenoma. The somatic nature of the three mutations was demonstrated.
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PMID:Novel canine tumour suppressor gene p53 mutations in cases of skin and mammary neoplasms. 1049 15

FHIT (fragile histidine triad), a candidate tumour suppressor gene, has recently been identified at chromosomal region 3p14.2, and deletions of the gene have been reported in many types of human cancer. However, the biological function of the Fhit protein has not been fully characterized yet. Using the yeast two-hybrid screen to search for proteins that interact with Fhit in vivo, we identified a protein that is specifically associated with Fhit. This association was confirmed in both immunoprecipitation and glutathione S-transferase pull-down assays. The sequence of the protein is identical with that of human ubiquitin-conjugating enzyme 9 (hUBC9). The last 21 amino acids at the C-terminus of hUBC9 appear to be unimportant for its biological activity, since an hUBC9 mutant harbouring a deletion of these amino acids could still restore normal growth of yeast containing a temperature-sensitive mutation in the homologue UBC9 gene. Mutational analysis indicated that hUBC9 was associated with the C-terminal portion of Fhit. Neither a single amino acid substitution at codon 96 (His-->Asn) nor triple amino acid substitutions (His-->Asn) at a histidine triad (codons 94, 96 and 98) affected the association, whereas Fhit triphosphate (diadenosine 5',5"'-P(1),P(3)-triphosphate) hydrolase activity has been reported to be eliminated by either type of mutation, suggesting that the interaction between Fhit and hUBC9 is independent of Fhit enzymic activity. Given that yeast UBC9 is involved in the degradation of S- and M-phase cyclins, Fhit may be involved in cell cycle control through its interaction with hUBC9.
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PMID:Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9. 1108 38

Rhabdoid tumours have been shown to carry somatic mutations in the INI1 (SMARCB1/hSNF5) gene. A considerable fraction of these tumours exhibit allelic losses on chromosome 22. Allelic loss on 22q also is characteristic for meningiomas, however most of these alterations are considered to be associated with mutations of the NF2 gene. We examined a series of 126 meningiomas for alterations in the INI1 gene. Four identical somatic mutations in exon 9 were detected resulting in an exchange of Arg to His in position 377 of INI1. Our observations were reproduced both by using DNA from a new round of extraction and by employing overlapping primers. This mutational hotspot therefore appears to be an important target in the formation of a fraction of meningiomas. In addition, 4 novel polymorphisms of INI1 were characterized. Our data indicate that the INI1 is a second tumour suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.
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PMID:INI1 mutations in meningiomas at a potential hotspot in exon 9. 1116 77

The Pfizer compound CP-31398 has been reported to stabilize the core domain of the tumour suppressor p53 in vitro and be an effective anti-cancer drug by virtue of rescuing destabilized mutants of p53. We did not detect any interaction between the p53 core domain and CP-31398 in vitro by a wide range of quantitative biophysical techniques over a wide range of conditions. CP-31398 did not stabilize p53 in our experiments. However, we found that CP-31398 intercalated with DNA and also altered and destabilized the DNA-p53 core domain complex. We analysed by NMR TROSY the interaction of the domain with a DNA oligomer and identified the changes in the complex on the binding of CP-31398. CP-31398 also decreased sequence-specific DNA binding of wild-type p53 and His-273 mutant p53. CP-31398 had a non-specific toxic effect independent of mutant p53 expression in several cell lines carrying Tet-regulated mutant p53. CP-31398 caused a small increase in MDM-2 expression and a more pronounced p53-independent increase in Bax expression. CP-31398 did, however, induce the PAb1620 epitope (characteristic of native p53) in cells expressing His-175 mutant p53. This was prevented by cycloheximide, suggesting that any stabilizing action of CP-31398 would have to be on newly synthesized p53. One of the unstable mutants that was reported to have been rescued by CP-31398, R249S, does not bind DNA when folded at lower temperatures.
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PMID:Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. 1194 95


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