Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclin kinase inhibitor WAF1/CIP1, also termed CDKN1, mediates p53-induced cell cycle arrest in response to DNA damage. This property makes it an attractive tumour-suppressor candidate for a p53-associated tumour-suppressor gene. In order to investigate the role of WAF1/CIP1 in the pathogenesis of primary human brain tumours we performed single-stranded conformation polymorphism (SSCP) analysis and direct sequencing of exon 2 of the gene in a representative series of 158 brain tumours and corresponding blood samples. In addition, all tumours were examined for mutations in exons 5-8 of the p53 gene. Analysis of WAF1/CIP1 revealed multiple polymorphisms, the most abundant being AGC-->AGA (Ser-->Arg) at codon 31 with an allele frequency of 8.5%. Less common polymorphisms included GTG-->GGG (Val-->Gly) at codon 25, GCC-->ACC (Ala-->Thr) at codon 64, CGC-->CTC (Arg-->Leu) at codon 32, GGC-->AGC (Gly-->Ser) at codon 14 and GCG-->GTG (Ala-->Val) at codon 39 each with an allele frequency of 0.3%. These polymorphisms were all located in a conserved region of exon 2. Two of the polymorphisms were also seen in a group of 157 healthy controls indicating that WAF1/CIP1 polymorphisms do not predispose to cancer. None of the tumours included in our series showed a somatic mutation in WAF1/CIP1. All samples were also analysed for loss of heterozygosity on the short arm of chromosome 6 in the region of the WAF1/CIP1 locus. Allelic loss was observed in only one patient with a glioblastoma. Mutations in the p53 gene were found in 22 of 158 tumours. No association was found between any polymorphism of the WAF1/CIP1 gene, p53 mutations and histopathological tumour type. Our data indicate that WAF1/CIP1 mutations are probably not involved in the formation of primary human brain tumours.
 ...
PMID:Multiple polymorphisms, but no mutations, in the WAF1/CIP1 gene in human brain tumours. 757 73

A close association of smoking-associated lung cancer incidence with the Msp 1 and 1le-Val polymorphisms of CYP1A1 gene was found in a Japanese population in terms of genotype frequency comparison and cigarette dose response. A synergistic increase in susceptibility to lung cancer was observed when the susceptible genotypes of CYP1A1 were combined with a deficient GSTM1 genotype. Individual difference in expression levels of Ahr and Arnt mRNAs was observed, and the expression levels of CYP1A1 appeared to associate with those of transcriptional factors. The Ahr protein has two different structures, ascribed to one amino acid replacement at codon 554 of Arg by Lys. However, this germ line polymorphism did not show a significant association with AHH inducibility nor lung cancer incidence. The p53 gene alterations in lung cancer tissues were more frequently observed among the patients with a susceptible allele of CYP1A1 gene.
 ...
PMID:Genetic polymorphisms of drug-metabolizing enzymes and lung cancer susceptibility. 758 93

The cellular content of mutant p53 and hsp72 proteins following gamma-ray irradiation, UV irradiation, and heat treatment was studied in A-7 cells, a human glioblastoma cell line. A-7 was found to contain a mutant p53 gene in which the arginine codon at position 175 was substituted by a histidine codon. Although the p53 gene was mutant, the phenotype of the p53 protein appeared wild-type since the cellular content of the p53 protein was limited under normal culturing conditions. The quantity of mutant p53 and hsp72 proteins in A-7 was increased by heat treatment as well as gamma-ray and UV irradiation. Furthermore, the mutant p53 protein was coimmunoprecipitated with anti-hsp72/hsc73 antibody. Additionally, hsp72 and hsc73 were coimmunoprecipitated with anti-p53 antibody. These results suggest that in A-7, p53 protein accumulation may be caused as a result of response to stressors, such as gamma-ray, UV and heat and that mutant p53 protein and hsp72/hsc73 may manage biological functions cooperatively after gamma-ray, UV and also heat treatments.
 ...
PMID:Accumulation of mutant p53 and hsp72 by heat treatment, and their association in a human glioblastoma cell line. 759 17

A mutation in the tumor suppressor p53 gene resulting in an Arg-->Ser substitution in position 249 is found frequently in human hepatocellular carcinomas associated with hepatitis B infection and with aflatoxin exposure. To determine the significance of this mutation in an in vivo experimental model using transgenic mice, we introduced a two-nucleotide change in the mouse p53 gene at amino-acid position 246, which is equivalent to position 249 in human p53, by the recombinant polymerase chain reaction mismatched primer method. This p53 mutation resulted in the same change, an Arg-->Ser substitution, as in the human p53 gene at position 249. We now report that the protein product of this mutant mouse p53ser246 had properties similar to those of the wild-type protein when tested by binding to (i) monoclonal antibodies PAb246 and PAb240, ii) simian virus 40 large T antigen, and (iii) heat-shock protein. However, it had mutant-type transforming properties when tested for colony formation with an osteosarcoma cell line. It was not active, as is wild-type p53, in transcription activation of the muscle creatine kinase promoter. These properties are the same as those found in the p53trp248 product of the p53 mutation associated with the Li-Fraumeni syndrome. Although less is known about the human p53ser249 product associated with hepatocellular carcinoma, the mutant murine p53ser246 protein shares the known properties of the human gene product.
 ...
PMID:Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. 760 78

Mutational inactivation of the p53 tumor suppressor gene is an infrequent event in human nasopharyngeal carcinoma (NPC), a malignancy showing a high incidence in southern China and southeast Asia. To examine the possible involvement of an activated p53 pathway in nasopharynx carcinogenesis, we have screened primary NPC biopsies for possible point mutations in WAF-1/CIP-1/p21, an effector gene transcriptionally regulated by and functioning as a mediator of the p53 tumor suppressor gene. Mutations in WAF-1/CIP-1/p21 might mimic p53 mutations in tumors having wild-type p53 such as most NPCs. The mutational analysis of WAF/CIP/p21 by PCR-single strand conformational polymorphism-direct sequencing revealed no point mutation in 41 primary NPC biopsies. A codon 31ser-->arg polymorphism was, however, detected. A striking difference in the distribution of the serine (WAF-ser) and arginine (WAF-arg) forms of WAF-1/CIP-1/p21 was observed when normal healthy Caucasians and Chinese were compared (P < 0.0001). The majority of Caucasians examined were found to be homozygous for WAF-ser (89%, n = 65), while Chinese living in areas of high NPC incidence show a greater than 86% homozygous or heterozygous WAF-arg (Taiwan, n = 66; Hunan, n = 32). The two forms of WAF-1/CIP-1/p21 were examined for potential functional differences in their ability to inhibit cyclin-dependent kinases and tumor cell growth. No significant differences were detected. Furthermore, no association between WAF-1/CIP-1/p21 genotype and NPC risk was observed in a case-control study of 76 NPC cases and 66 normal controls conducted in Taiwan.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:No point mutation but a codon 31ser-->arg polymorphism of the WAF-1/CIP-1/p21 tumor suppressor gene in nasopharyngeal carcinoma (NPC): the polymorphism distinguishes Caucasians from Chinese. 760 1

Three different p53 polymorphisms (a codon 72 BstUI RFLP, a 16-bp duplication in intron 3 and an MspI RFLP in intron 6) and haplotype combinations were studied in three northern European populations, viz. Finns, Swedes and Swedish Saamis. Significant ethnic differences were found in the codon 72 and 16-bp polymorphisms. The three polymorphisms were in strong linkage disequilibria, all of which were highly significant (p < 1 x 10(-18)), and ethnic differences with respect to linkage disequilibria were observed. Estimates of the frequencies of extended haplotypes showed that the most common ('wild-type') haplotype in the three populations was 2-1-2, viz, the codon 72 Arg allele linked to absence of the 16-bp duplication and presence of the MspI site. There were two additional common haplotypes, 1-1-2 and 1-2-1, and five rare haplotypes with a combined frequency of about 0.03. The present results indicate that extended haplotypes would be more informative in studies of population differences and associations between p53 germline mutations and cancer.
 ...
PMID:p53 polymorphisms and haplotypes in different ethnic groups. 761 99

Previous work has shown that a fusion protein bearing a "nonremovable" N-terminal ubiquitin (Ub) moiety is short-lived in vivo, the fusion's Ub functioning as a degradation signal. The proteolytic system involved, termed the UFD pathway (Ub fusion degradation), was dissected in the yeast Saccharomyces cerevisiae by analyzing mutations that perturb the pathway. Two of the five genes thus identified, UFD1 and UFD5, function at post-ubiquitination steps in the UFD pathway. UFD3 plays a role in controlling the concentration of Ub in a cell: ufd3 mutants have greatly reduced levels of free Ub, and the degradation of Ub fusions in these mutants can be restored by overexpressing Ub. UFD2 and UFD4 appear to influence the formation and topology of a multi-Ub chain linked to the fusion's Ub moiety. UFD1, UFD2, and UFD4 encode previously undescribed proteins of 40, 110, and 170 kDa, respectively. The sequence of the last approximately 280 residues of Ufd4p is similar to that of E6AP, a human protein that binds to both the E6 protein of oncogenic papilloma viruses and the tumor suppressor protein p53, whose Ub-dependent degradation involves E6AP. UFD5 is identical to the previously identified SON1, isolated as an extragenic suppressor of sec63 alleles that impair the transport of proteins into the nucleus. UFD5 is essential for activity of both the UFD and N-end rule pathways (the latter system degrades proteins that bear certain N-terminal residues). We also show that a Lys --> Arg conversion at either position 29 or position 48 in the fusion's Ub moiety greatly reduces ubiquitination and degradation of Ub fusions to beta-galactosidase. By contrast, the ubiquitination and degradation of Ub fusions to dihydrofolate reductase are inhibited by the UbR29 but not by the UbR48 moiety. ufd4 mutants are unable to ubiquitinate the fusion's Ub moiety at Lys29, whereas ufd2 mutants are impaired in the ubiquitination at Lys48. These and related findings suggest that Ub-Ub isopeptide bonds in substrate-linked multi-Ub chains involve not only the previously identified Lys48 but also Lys29 of Ub, and that structurally different multi-Ub chains have distinct functions in Ub-dependent protein degradation.
 ...
PMID:A proteolytic pathway that recognizes ubiquitin as a degradation signal. 761 50

The effect of the expression of the exogenous human mutant p53 (Arg-->His in codon 273) on the amplification rate of the gene dhfr in permissive Rat-1 and LIM1215 cells was studied. It was shown that injection of a retroviral construction with p53His273 resulted in the accumulation of methotrexate-resistant variants with an increased number of dhfr copies in populations of recipient cells. Luria-Delbruck fluctuation analysis revealed a four- to six-fold increase in the rate of appearance of new methotrexate-resistant cells. Chromosomal analysis demonstrated an extrachromosomal location of amplified DNA in cells containing p53His273, as was the case for control sublines. The data obtained indicate that modifications of p53 may induce gene amplification not only via removing the proliferation block of cells with amplified genes in selective medium, but also via some other mechanisms, that seem to increase the chromosomal recombination rate.
 ...
PMID:[p53 with a mutation in codon 273 increases the probability of amplifying the dhfr gene in Rat-1 and LIM1215 cells]. 762 24

Twenty-one invasive squamous-cell carcinomas (SCC) of the bladder from Schistosoma-hematobium-infected patients were examined immunohistochemically for the expression of p53, Rb, EGFR and c-erbB-2 proteins; and screened by single-strand conformation polymorphism and sequencing for mutations in the ras (H, N, K) codon hotspots (12, 13, 61) and p53 (exons 4-9) genes. Positive staining for p53, EGFR and c-erbB-2 was reported in 38, 67 and 28% of tumors respectively. Only one of the tumors, the only one that was poorly differentiated, displayed an absence of nuclear Rb staining. Ras alterations were detected in the H-ras gene in 3 tumors, 2 of which harbored a codon-13 (Gly-->Arg) and one a codon-12 (Gly-->Ser) point mutation. p53 mutations were recorded in 12 tumors (57%), 6 of which stained positively for p53. Four tumors had exon-7 mutations (codons 235, 241 and 249; one tumor had 2 exon-7 mutations). Eight tumors were mutated in exon 8 (codons 264, 271, 273, 285, 286, 288 and 294), 5 of which harbored multiple mutations. One tumor had an insertion/deletion event in exon 9. The frequency of detection of over-expression of EGFR and c-erbB-2 in bilharzial-bladder lesions is comparable to that reported in TCC, contrasting with the infrequent loss of Rb expression found in invasive lesions associated with schistosomiasis infection. However, the detection of multiple p53 mutations in these lesions is suggestive of the involvement of a carcinogenic agent with maintenance of preferential activation of the H-ras gene.
 ...
PMID:Molecular events underlying schistosomiasis-related bladder cancer. 762 66

Partial sequence determinations were performed on exon 8 of tumour suppressor gene p53 of cattle, sheep, goat, horse and pig. High sequence homology between these species and other species including dog, cat, chicken and man is demonstrated. A mutation CGG-->TGG (arginine-->tryptophan) was detected in a feline solid carcinoma of the mammary gland.
 ...
PMID:Sequence of an exon of tumour suppressor p53 gene--a comparative study in domestic animals: mutation in a feline solid mammary carcinoma. 764 Sep 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>