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

Kidney and esophageal tumors induced by alkylating N-nitroso compounds in rats contain a high incidence (75-100%) of G----A transition mutations in the p53 gene. These are almost selectively (89%) located in the first base of codon 204 and the second base of 213, leading to amino acid substitutions Glu----Lys and Arg----Gln, respectively. In contrast to human neoplasms, a considerable fraction of rat kidney and esophageal tumors carries multiple p53 mutations. All nephroblastomas induced by transplacental exposure to N-nitrosoethylurea and 56% of esophageal tumors induced by N-nitrosomethylurea showed double mutations in codons 204 and 213 of exon 6. The selective targeting of p53 codons by alkylating nitrosamines may provide a basis for molecular epidemiological studies on this class of chemical carcinogens.
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PMID:Selective mutation of codons 204 and 213 of the p53 gene in rat tumors induced by alkylating N-nitroso compounds. 131 33

A patient with bilateral retinoblastoma and subsequent multiple primary osteosarcomas has been described previously. Osteosarcoma cell lines established from this patient were shown to express a shortened RB1 mRNA transcript and no detectable normal Rb protein. We now show that the osteosarcoma cell lines have lost one TP53 allele and contain a mutation in exon 8 codon 286 [GAA to AAA (Glu to Lys)] in the remaining allele. Consequently, the osteosarcoma cell lines have no normal Rb protein and no normal p53 protein. Neither constitutional DNA nor DNA extracted from a retinoblastoma of the left eye of the patient contained the TP53 mutation, suggesting that the TP53 mutation in the osteosarcoma cells may represent a tumor-promoting mutation, which confers a selective growth advantage. If both RB1 and TP53 are involved in the initiation of osteosarcoma, the mechanisms for development of the retinoblastoma and osteosarcoma tumors are different.
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PMID:A TP53 mutation detected in cells established from an osteosarcoma, but not in the retinoblastoma of a patient with bilateral retinoblastoma and multiple primary osteosarcomas. 133 9

Human DNA-PK is a nuclear, serine/threonine protein kinase that, when activated by DNA, phosphorylates several DNA-binding substrates, including the tumor suppressor protein p53. To identify which p53 residues are phosphorylated, we examined DNA-PK's ability to phosphorylate synthetic peptides corresponding to human p53 sequences. Serines 15 and 37 in the amino-terminal transactivation domain of human p53, and serines 7 and 18 of mouse p53, were phosphorylated by DNA-PK in the context of synthetic peptides. Other serines in these p53 peptides, and serines in other p53 peptides, including peptides containing the serine 315 p34cdc2 site and the serine 392 casein kinase II site, were not recognized by DNA-PK or were phosphorylated less efficiently. Phosphorylation of the conserved serine 15 in human p53 peptides depended on the presence of an adjacent glutamine, and phosphorylation was inhibited by the presence of a nearby lysine. Phosphorylation of recombinant wild-type mouse p53 was inhibited at high DNA concentrations, suggesting that DNA-PK may phosphorylate p53 only when both are bound to DNA at nearby sites. Our study suggests that DNA-PK may have a role in regulating cell growth and indicates how phosphorylation of serine 15 in DNA-bound p53 could alter p53 function.
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PMID:Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53. 140 79

Human cyclin B1-bound cdc2 kinase phosphorylated the threonine residue in the sequence -Thr-Pro-Lys-Lys-Ala- but hardly phosphorylated it in the sequence -Thr-Pro-Lys-Ala-Lys. The sequence -Thr-Pro-Ala-Pro-Lys-, as found in p53 protein, was also phosphorylated by this enzyme, but less efficiently than in the sequence described above. When the threonine residue in -Thr-Pro-Lys-Lys-Ala- was changed to a serine or a tyrosine residue, the enzyme phosphorylated the serine, but not the tyrosine residue. Changing the lysine next to the proline to alanine reduced its efficiency as a substrate. The peptide, Ala-Ala-Ala-Ala-Lys-Thr-Pro-Ala-Lys-Ala-Ala, containing the -Thr-Pro-Ala-Lys- sequence, but not the other lysine residues, was not used as a substrate by the kinase.
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PMID:Preference of human cdc2 kinase for peptide substrate. 145 May 22

The expression of the nuclear phosphoprotein p53 was studied immunohistochemically in a series of 150 benign and malignant colorectal tumors. Using monoclonal antibody PAb1801, tumors divided unequivocally into two groups on the basis of immunohistochemistry. Forty of the carcinomas (46.5%) showed positive staining but only 4 of the adenomas (8.7%) were positive (P less than 0.001). The few positive adenomas always showed moderate or severe dysplasia. Metaplastic polyps (n = 9) and small familial adenomatous polyposis-related adenomas (n = 9) were uniformly negative. Carcinomas with p53 expression did not differ from those without in terms of site, differentiation or the prognostic indicators of Dukes' stage, DNA ploidy, or tumor histology. The improved morphologic resolution available in periodate lysine paraformaldehyde dichromate (PLPD)-fixed, paraffin-embedded tissue permitted several conclusions to be made: p53 is confined to neoplastic nuclei; staining in positive tumors is heterogeneous and often more marked at the infiltrative margins; and staining intensity is dramatically reduced in mitotic cells. It is concluded that expression of immunohistochemically detectable p53 (probably representing mutated forms of the protein) occurs in some adenomas around the time of transition to carcinoma. Therefore there is an association with the appearance of infiltrative behavior but not with degree of tumor progression (including metastasis) at the time of resection.
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PMID:p53 expression in colorectal tumors. 170 33

We have examined the large T encoded by an SV40 mutant, d10, which fails to localize to the nucleus. The DNA sequence of the mutant predicts the alteration of Lys 128----Thr within the sequence 127 Lys Lys Lys Arg Lys 131 of large T. The results show that d10 large T is capable of binding to SV40 DNA, to cellular DNA and to the cellular phosphoprotein p53 as well as wild-type large T. These data suggest that the cytoplasmic location of d10 large T is not due to an inability of the protein to be retained within the nucleus, but argues instead that the protein fails to reach the nucleus because it contains a defective nuclear location signal.
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PMID:The abnormal location of cytoplasmic SV40 large T is not caused by failure to bind to DNA or to p53. 300 45

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.
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PMID:Genetic polymorphisms of drug-metabolizing enzymes and lung cancer susceptibility. 758 93

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.
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PMID:A proteolytic pathway that recognizes ubiquitin as a degradation signal. 761 50

Critical determinants of DNA recognition by p53 have been identified by a molecular genetic approach. The wild-type human p53 fragment containing amino acids 71 to 330 (p53(71-330)) was used for in vitro DNA binding assays, and full-length human p53 was used for transactivation assays with Saccharomyces cerevisiae. First, we defined the DNA binding specificity of the wild-type p53 fragment by using systematically altered forms of a known consensus DNA site. This refinement indicates that p53 binds with high affinity to two repeats of PuGPuCA.TGPyCPy, a further refinement of an earlier defined consensus half site PuPuPuC(A/T).(T/A) GPyPyPy. These results were further confirmed by transactivation assays of yeast by using full-length human p53 and systematically altered DNA sites. Dimers of the pentamer AGGCA oriented either head-to-head or tail-to-tail bound efficiently, but transactivation was facilitated only through head-to-head dimers. To determine the origins of specificity in DNA binding by p53, we identified mutations that lead to altered specificities of DNA binding. Single-amino-acid substitutions were made at several positions within the DNA binding domain of p53, and this set of p53 point mutants were tested with DNA site variants for DNA binding. DNA binding analyses showed that the mutants Lys-120 to Asn, Cys-277 to Gln or Arg, and Arg-283 to Gln bind to sites with noncanonical base pair changes at positions 2, 3, and 1 in the pentamer (PuGPuCA), respectively. Thus, we implicate these residues in amino acid-base pair contacts. Interestingly, mutant Cys-277 to Gln bound a consensus site as two and four monomers, as opposed to the wild-type p53 fragment, which invariably binds this site as four monomers.
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PMID:Discrimination of DNA binding sites by mutant p53 proteins. 765 37

The tumor suppressor gene p53 plays a critical role in the cellular response to genetic damage caused by radiation. In addition, mutations in this gene are often encountered in cells in lung tumors resected from uranium miners whose exposure to radon daughters exceeded 450 working level months. However, most of these miners also smoked tobacco products. Thus whether this gene is of specific importance in lung cancer is unclear. In this study, aberrations in the p53 gene were investigated using an immunohistochemical assay on 38 lung tumors (26 squamous cell carcinomas, 9 adenocarcinomas and 3 adenosquamous carcinomas) from rats that had inhaled 239PuO2 aerosols. Only 2 tumors exhibited detectable levels of staining of p53 products; both were large, well-differentiated squamous cell carcinomas that had invaded the pleural cavity or mediastinum. Direct DNA sequence analysis was used to characterize the mutations in these two tumors, and both exhibited G-->A transition mutations. One tumor was mutated in the first position of codon 283, resulting in a lysine for glutamine substitution; the other tumor was mutated at the second position of codon 280, resulting in a histidine to arginine substitution. No alterations in exons 5-7 of the p53 gene were found in a representative sample of tumors that did not exhibit elevated levels of the protein by immunohistochemistry. Further, no detectable polymorphisms or deletions were observed within the rat p53 gene after Southern blot analysis of 18 randomly selected 239Pu-induced tumors. These results suggest that p53 mutations are relatively unimportant in the development of lung tumors induced in the rat by high-linear energy transfer radiation.
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PMID:p53 alterations in plutonium-induced F344 rat lung tumors. 776 75


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