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)

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

The codon 31 polymorphism of the p53-inducible protein p21 was studied with respect to allele frequency variations between some major ethnic groups. The frequency of the Al (Arg) allele showed highly significant variations ranging from 4% in Caucasians (Swedes) to 50% in Chinese. Compared to Caucasians, a relatively high frequency was found in African Blacks (29%) and Indians (16%). Furthermore, Finns and Mordvinians also had higher frequencies (9-10%) than west Europeans (French and Swedes), consistent with an Asiatic Mongoloid influence known to exist in Finno-Ugrian tribes. The geographic allele frequency patterns of p53 and its effector protein p21 were quite different. The p21 A1 mutations in African, Asiatic and European populations were identical at the DNA level. The geographical distribution of the A1 allele suggests an independent origin in Africa and Asia. The very pronounced ethnic differentiation of tumour suppressor genes and the fact that tumour suppressor genes may be teratogenes suggest that these polymorphisms are maintained by natural selection, probably operating in the intrauterine period.
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PMID:The codon 31 polymorphism of the p53-inducible gene p21 shows distinct differences between major ethnic groups. 886 9

Highly conserved regions of the tumour suppressor gene p53, including the typical human tumour hot spots (codons 175, 245, 248, 249, 273 and 282), were investigated in various canine neoplasms. A mutation CGG-->TGG (arginine-->tryptophan) was detected in codon 249 in an adenoma of the circumanal gland.
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PMID:Canine tumour suppressor gene p53--mutation in a case of adenoma of circumanal glands. 923 81

p53 is a tumour suppressor gene which functions as a transcription factor to upregulate genes for growth arrest and apoptosis following DNA damage. p53 mutations are associated with Li-Fraumeni and Li-Fraumeni like syndromes. Recently mutations of the oligomerization domain have been isolated from an LFS and an LFL family affecting respectively codon 344 (Leu to Pro) and 337 (Arg to Cys). The present study was designed to determine the affect of these mutations on the function of p53 protein. p53 344 Leu to Pro existed only in a monomeric form and could not bind to DNA. It was inactive at inducing apoptosis, transactivating luciferase from a bax promoter and inhibiting cell growth. In contrast, p53 337 Arg to Cys could form tetramers and could bind to DNA. However, p53 337 Arg to Cys was not fully active and could only induce apoptosis, transactivate luciferase from a bax promoter and inhibit cell growth with approximately 60% of the ability of wild-type p53. Both mutant proteins had reduced ability to bind to MDM2, p53 337 Arg to Cys being more reduced than p53 344 Leu to Pro. These results indicate that point mutations in the oligomerization domain can disrupt p53 function. In addition, the value of LFS and LFL families for the further understanding of the biological and biochemical properties of p53 is demonstrated.
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PMID:Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members. 970 30

Eighteen human congenital melanocytic naevi (CMN) from 17 patients were screened for activating point mutations in the oncogenes N-ras and CDK4 and for sequence variants in the MC1R gene by combined RFLP-PCR/SSCP analysis. In addition, all lesions were screened for deletions and point mutations in the tumour suppressor genes p53 and p16INK4a (CDKN2A) by combined multiplex PCR/SSCP analysis. Positive screening data were specified by sequencing of the corresponding PCR product. Activating point mutations in the N-ras gene (nine CAA (Gln) to AAA (Lys) transversions and one CAA (Gln) to CGA (Arg) transition at codon 61) were detected at high frequency (56%). Furthermore, three missense mutations (V92M) and two silent mutations (CGA (Arg) to CGG (Arg), codon 213, exon 6) were found in the MC1R and p53 genes, respectively. No mutations were found in p16 or CDK4. The activated N-ras oncogene, which is also found in human cutaneous melanomas, may constitute a potential risk factor for melanoma formation within CMN.
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PMID:Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi. 1046 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

Squamous cell lung carcinomas (SCC) from former employees of the Wismut uranium mining company (Saxony, Germany) were obtained from the Stollberg Archive in order to screen for p53 tumour suppressor gene codon 249 arg-->met hotspot mutations, a putative molecular bio-dosimeter of alpha-particle (radon) exposure (Taylor et al (1994) Lancet 343: 86-87; McDonald et al (1995) Cancer Epidemiol Biomarkers Prevent 4: 791-793). Of the 29 archived samples of SCC meeting quality criteria for DNA analysis by polymerase chain reaction (PCR) and Haelll restriction enzyme digestion, two tumours were found that harboured this mutation. DNA sequencing confirmed the presence of a G to T base substitution within the Haelll site spanning codons 249 and 250 of the p53 gene that results in replacement of arginine (wild-type) by methionine at residue 249. When these data are combined with those from our previous study of tumours from the Stollberg Archive in which 50 lung tumours were examined, (including nine SCCs), we conclude that the G-->T (arg-->met) codon 249 mutation prevalence in the Wismut miner cohort is not sharply elevated in lung cancers in general (two mutations/79 tumours), or specifically in SCCs of the lung (two mutations/38 SCC) when compared to data from lung cancer patients with no reported occupational exposure to radon gas.
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PMID:Analysis of radon-associated squamous cell carcinomas of the lung for a p53 gene hotspot mutation. 1073 42

Mutation of p53, a tumour suppressor gene, is uncommon in cervical cancer but the detection of human papillomavirus (HPV) DNA in cervical cancer is common. The findings of increased susceptibility to degradation of p53 by E6 protein of HPV16/18 in cervical cancer with homozygous arginine at codon 72 (HA72) of p53 led to this study on whether cervical cancers with HA72 were more aggressive with the increase in the rate of loss of p53 function. In 102 cervical cancers, 76.5% were HPV16/18 positive and 30% had HA72. No survival difference was detected between HA72 and non-HA72 tumours irrespective of HPV16/18 status. Furthermore, the detection of HPV16/18 in cervical cancer was found not to be of prognostic significance in this study.
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PMID:Homozygous arginine at codon 72 of p53 has no prognostic significance in cervical cancer. 1075 63

The INK4a/ARF locus encodes two distinct tumour suppressors, p16INK4a and p14ARF, that regulate cell cycle progression via the pRB and p53 pathways, respectively. The ARF protein inhibits hdm2 activity, leading to the stabilization of the p53 tumour suppressor and cell cycle inhibition. The amino-terminal domain of human p14ARF and of the mouse homologue, p19ARF, is sufficient for these effects. This domain is also sufficient for the nucleolar localization of the mouse ARF protein. In contrast, we show that the human ARF protein requires two arginine rich domains, one in the amino- and the other in the carboxy-terminus, for nucleolar targeting. The amino-terminal nucleolar-targeting domain of p14ARF is also important for ARF-hdm2 binding and cell cycle inhibition. The carboxy-terminal p14ARF nucleolar localization domain lies within the shared INK4a/ARF exon 2, and is mutated in a small number of melanoma-prone kindreds. The INK4a/ARF exon2-mutations could affect the function of both the p16INK4a and p14ARF tumour suppressors. Oncogene (2000).
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PMID:Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization. 1087 49

As concerns human adult brain neoplasms, the biological behaviour of glioblastoma, a high-grade neuro-ectodermal tumour, is among the most disadvantageous. Glioblastoma may develop either as a primary tumour without clinical and histological evidence of a prior precursor lesion, or as the final stage of malignant transformation of a low-grade or anaplastic astrocytoma. There are conflicting reports in connection with the association of the p53 tumour suppressor gene mutation with the clinical and histological progression of gliomas. Previous studies likewise led to contradictory results concerning the significance of ras oncogenes in different histological malignancies, and especially in neuro-epithelial tumours. The possible roles of p53 and ras gene alterations in the development of "primary" and "transformed" glioblastomas were studied in this work. Eighteen tumours were investigated by means of immunohistochemistry and polymerase chain reaction-assisted-single strand conformation polymorphism (PCR-SSCP) sequence analysis in a search for molecular genetic differences between primary and transformed glioblastomas. An increased incidence of p53-immunopositive cells was observed in both types of glioblastomas but there was no significant difference between the transformed tumours and the primary form. All samples were screened for point mutation in codons 12 and 61 of the H-, K-, and N-ras oncogenes and exons 5-8 of the p53 gene. No aberrant band or mutation was found in the H-, K- and N-ras oncogenes. Aberrant bands were seen in only 2 (11%) of the 18 tumours in the SSCP analyses of exons 6 and 8. Sequence analysis of the 2 abnormal cases revealed G --> C transmission in the second nucleotide of codon 280 on exon 8, which resulted in a change in the encoded amino acid from arginine to threonine (case 15). A ttagtct --> ttggtct transmission on intron 5 (case 8) was also found. No genetic difference could be identified between the primary and the transformed glioblastoma forms as concerns their p53 and ras oncogenes. There are two possible explanations for these findings: (a) The p53 and ras gene mutations were not primary events in the morphological transformations. Alterations in these genes may therefore take place at an early stage in glioma progression. (b) The different genetic changes may accumulate during glioblastoma development. These specific genetic events may additionally play a role in multistep tumourigenesis.
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PMID:Sporadic p53 mutations and absence of ras mutations in glioblastomas. 1092 24


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