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)

We report a constitutional point mutation of codon 278 in exon 8 of the TP53 gene that has not yet been described as a germ-line mutation. A 52-year-old female developed multiple primary malignancies (liposarcoma, breast cancer, malignant histiocytoma, occult adenocarcinoma). The mutation found in her tumour and peripheral blood lymphocyte DNA is a cytosine to thymine transition at the second position of codon 278 resulting in an amino acid exchange from proline to leucine in the DNA-binding domain. Evaluation of the patient's family revealed that both of her sons were affected by the same mutation. Although the patient's mother had died already, we were able to demonstrate by polymorphic microsatellite analysis that the defective allele originated from the maternal side. As four brothers and one sister had inherited the same allele, which however was wild type, we were able to show that the mutation must have occurred in the germ cells of the patient's mother and that it may therefore be called de novo. This explains the lack of a high cancer incidence in the family history. All tumours tested showed positive immunohistochemical staining for p53. Loss of heterozygosity was found in five of seven tumours, one showing chromosome 17 monosomy.
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PMID:A constitutional de novo mutation in exon 8 of the p53 gene in a patient with multiple primary malignancies. 868 34

Germline mutations in the p53 tumor suppressor gene are associated with the Li-Fraumeni syndrome, characterized by childhood sarcoma, leukemia and early onset breast cancer and has occasionally been found also in familial breast-ovarian cancer. Most mutations found are of missense type and located in the central region of the gene (exons 5 to 8). In the present study, a germline p53 alteration was identified in a late onset breast cancer family (kindred Lund 5; mean age 58 years) using single stranded conformation polymorphism and sequence analysis. The mutation (a CCG to CTG transition) at codon 82 in exon 4, resulting in a proline to leucine substitution, has not previously been reported and was not present in a control set of 60 healthy individuals. Three of five woman with breast cancer (45, 57 and 65 years) were carriers of the alteration. Loss of heterozygosity at the p53 locus was not seen in the primary tumors of these women, but appeared as a partial loss of the wildtype allele in subsequent recurrent lesions of two gene carriers. The family manifested no linkage to the p53 gene (a two-point LOD-score of -0.41), and has previously also been excluded for linkage to the BRCA1 and BRCA2 loci, as well as being carrier of a BRCA1 germline mutation. Although it seems unlikely that the p53 germline mutation is the major cause of disease predisposition in Lund 5, the data suggest that some p53 alteration may confer a subtle influence on breast cancer development and progression.
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PMID:A novel p53 germline alteration identified in a late onset breast cancer kindred. 871 Mar 80

Proteases are known to be involved in the apoptotic pathway. We report here that benzyloxycarbonyl (Z)-Leu-Leu-leucinal(ZLLLal), a leupeptin analogue, can induce apoptosis in MOLT-4 and L5178Y cells. ZLLLal is a cell-permeant inhibitor of proteasome. Among the protease inhibitors tested, only calpain inhibitor I (acetyl-Leu-Leu-norleucinal) and ZLLLal caused a marked induction of apoptosis in MOLT-4 cells. In contrast Z-Leu-leucinal, a specific inhibitor of calpain, did not induce apoptosis. When MOLT-4 cells were incubated in the presence of ZLLLal, p53 accumulated in the cells. These results strongly suggest that inhibition of proteasome induces p53-dependent apoptosis and that proteasome can protect cell from apoptosis.
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PMID:Apoptosis induction resulting from proteasome inhibition. 871 62

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

Human papilloma virus (HPV) type 16 has an established association with anogenital carcinoma, and to some extent with human oral squamous cell carcinoma. We hypothesize that HPV type 16 is capable of inducing chromosomal and cell cycle changes in cultured oral epithelial cells. Normal human oral epithelia] cells were immortalized with recombinant retrovirus containing the E6/E7 open reading frames of HPV type 16. These cells have been in culture for more than 350 passages and over 4 years. Flow cytometry demonstrated an average of 42% nuclear aneuploidy in HPV 16-immortalized cells; 16% in normal controls (probably tetrasomy). Cytogenetic analysis demonstrated significant progression of chromosomal abnormalities. Cells at early passage (p10) showed trisomy 20, with no other major changes. At passage 18, trisomy 1q and monosomy 13 were seen in addition to trisomy 20. At passage 61 there were two distinct cell populations ('a' and 'b'), with multiple chromosomal changes including trisomy 5q,14,20 in one line and 7p,9q,llq in the other. Both populations had monosomy 3p, with monosomy 8p in one population and monosomy 13 in the other. At passage 136, the cells were essentially identical to population 'b' of passage 61. At this passage, mutation of the p53 gene was detected at codon 273 of exon 8, with G to T conversion (Arg to Leu). This was absent in the normal cells from which this line was developed. Passage 262 contained the two major cell populations, each with a sub-group with additional chromosomal changes such as 10p monosomy. Cells from passages 217 and 305 were injected into nude mice a year apart. Both failed to produce tumors, as did normal cells. In conclusion, we present an HPV type 16-immortalized oral epithelial cell line (IHGK) with extensive and progressive chromosomal abnormalities, invasive growth in culture and yet no tumor formation in nude mice. We suggest that the question as to whether HPV alone can induce transformation is still open.
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PMID:Chromosomal abnormalities in HPV-16-immortalized oral epithelial cells. 882 27

The effect of a calpain-selective cell permeant inhibitor, benzyloxycarbonyl Leu-Leu-Tyr diazomethylketone (ZLLY-CHN2), on the serum-stimulated growth of WI-38 human fibroblasts has been investigated. Only cell permeant protease inhibitors with activity against calpains prevented progression into S-phase. Protein blotting experiments indicated that p53 immunoreactivity increased in late G1 cells treated with ZLLY-CHN2. The content of p21Waf1/Cip1 CDK inhibitor also increased, providing a mechanism for the observed failure to enter S-phase. Further studies indicated that p53 could be degraded by a ZLLY-CHN2-sensitive protease immediately prior to S-phase, but that proteolysis did not occur after this critical time point. Chelation of extracellular Ca2+ by addition of EGTA inhibited the p53 degradation. Consistent with proteolysis of p53 in late G1 phase, mu-calpain immunoreactivity transiently accumulated in cell nuclei at this time. ZLLY-CHN2 did not appear to increase p53 mRNA in WI-38 cells. Purified mu-calpain required only 1 to 3 microM Ca2+ to proteolyze p53 in WI-38 cell lysates. These results indicate that ZLLY-CHN2 inhibits progression of WI-38 cells into S-phase by inactivating a calpain-like protease that is responsible for proteolysis of constitutively expressed p53 in late G1.
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PMID:Inhibition of the growth of WI-38 fibroblasts by benzyloxycarbonyl-Leu-Leu-Tyr diazomethyl ketone: evidence that cleavage of p53 by a calpain-like protease is necessary for G1 to S-phase transition. 901 11

Paraffin embedded tissue of 84 oligodendrogliomas (63 primary tumours, 21 recurrences), 21 glioblastomas with oligodendroglial growth pattern (15 primaries, 6 recurrences) and 17 mixed gliomas was investigated for the presence of mutations in exons 5-9 by means of single stranded conformation polymorphism (SCCP), temperature gradient gel electrophoresis (TGGE) and direct DNA sequencing. In parallel, p53 protein accumulation was determined by means of immunohistochemistry. The percentage of mutations was found to be higher than previously reported (6 of 44 grade II oligodendrogliomas, 4 of 19 grade III oligodendrogliomas, 4 of 15 glioblastomas). In 4 cases, the mutations lead to distinct changes in the primary or secondary structure of the protein (cysteine-->tyrosine, proline-->leucine) and were associated with marked accumulation of p53 protein. A significant correlation between p53 protein accumulation and TP53 gene aberrations was found (P < 0.001), although p53 protein accumulation was detected more often than TP53 gene anomalies, indicating that factors other than TP53 gene mutation may also lead to a p53 protein accumulation in the tumour cells. A significant correlation was found for p53 protein accumulation and tumour grade but not TP53 gene mutations. In conclusion, evaluation of p53 protein accumulation reflected the clinical course of oligodendrogliomas better than the mere presence of TP53 gene mutations.
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PMID:Demonstration of p53 protein and TP53 gene mutations in oligodendrogliomas. 903 5

Merkel cell carcinoma is a very rare tumor. This is why it is not known whether this neoplasm behaves differently in the vulvar location than at other sites. We present a patient with a Merkel cell carcinoma assessed with a light optical microscope, immunohistochemistry, and electron microscope. Only eight previous cases have been reported in the literature. We discuss pathologic findings, such as histologic trabecular pattern under the optical microscope and neurosecretory granules (similar to Merkel cell carcinoma of the skin) under the electron microscope. Also discussed are the results of immunohistochemistry for low-molecular-weight cytokeratin, neuron-specific enolase, chromogranin, and Leu 7, and molecular study of N-ras, K-ras, N-myc, and p53 genes. Little is known about Merkel cell carcinoma of the vulva, but it seems to have a more aggressive behavior and poorer prognosis than Merkel cell carcinoma at other sites.
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PMID:Merkel cell carcinoma of the vulva. 906 65

Decorin belongs to a family of secreted, small, leucine-rich proteoglycans that affect matrix assembly and cellular growth. Ectopic expression of decorin proteoglycan or protein core as a mutated form lacking any glycosaminoglycan side chains induced growth suppression in neoplastic cells of various histogenetic origins, including tumor cells derived from gastrointestinal, genital, skeletal, cutaneous, or bone marrow tissues. Exogenously added recombinant decorin also suppressed overall growth of the parental cell lines. In all stably-transfected clones, growth retardation was specifically associated with induction of the potent cyclin-dependent kinase inhibitor p21, but not p27, and subsequent translocation of p21 protein into the nuclei of decorin-expressing cells. This led to a greater proportion of the cells arrested in G1 phase of the cell cycle. These changes were independent of functional p53 or retinoblastoma protein. De novo expression of decorin in HCT116 human colon carcinoma cells harboring a disrupted p21 gene failed to induce growth suppression, in contrast to the wild-type cells in which p21 and growth arrest could be induced. These findings indicate that ectopic production of decorin protein core can retard the growth of a variety of tumor cells and that endogenous p21 is a required downstream effector of this biological axis.
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PMID:Ectopic expression of decorin protein core causes a generalized growth suppression in neoplastic cells of various histogenetic origin and requires endogenous p21, an inhibitor of cyclin-dependent kinases. 920 67

Male F-344 rats were fed for 15 weeks a methyl-deficient L-amino acid defined diet containing 0.05% DL-ethionine. Nodules protruding from the surface of the liver were dissected free of surrounding tissue, and polyadenylated RNA isolated from the nodules was reverse transcribed. The region of the p53 gene comprising codons 120-290 was amplified by the polymerase chain reaction, and cDNAs were sequenced. Mutations were detected in nodules obtained from 7 of 12 rats. In all seven cases, the same two point mutations were present. The first was at the first base of codon 246 and consisted of a C-->T transition (C:G-->T:A, Arg-->Cys), while the second was at the second base of codon 247 and consisted of a G-->T transversion (G:C-->T:A, Arg-->Leu). It is concluded that the hepatocarcinogen ethionine induces specific hot-spot p53 gene mutations; this is in contrast to the mutations at various sites previously observed to occur in rats fed a hepatocarcinogenic methyl-deficient diet alone. The results also provide the first evidence that ethionine is mutagenic in the rat.
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PMID:Hot-spot mutations in the p53 gene of liver nodules induced in rats fed DL-ethionine with a methyl-deficient diet. 921 26


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