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)

Molecular mechanisms of pituitary tumorigenesis were studied using Polymerase chain reaction-single stranded conformational polymorphism with DNA sequencing to identify potential mutations in the ras protooncogenes and the tumor suppressor gene p53 in invasive pituitary adenomas and carcinomas. Sequencing of exons 5 through 8 of the p53 gene revealed no mutations, nor were mutations detected in the N- or K-ras protooncogenes in four of the carcinomas and their respective metastatic deposits. Point mutations of H-ras however, were identified in three distant metastatic pituitary tumor secondaries, but not in their respective primary pituitary carcinomas, or in six invasive adenomas. Two of the mutations included a G to C substitution at codon 12, and a G to A substitution at codon 18, resulting in a glycine to arginine, and an alanine to threonine change at these amino acids, respectively. A third mutation involved a single base pair (adenine) deletion in codon 3 of H-ras which causes a frame shift, resulting in a termination signal at codon 19. These results suggest that point mutations in p53 and ras are not associated with pituitary tumorigenesis, however, point mutations of the H-ras gene may be important in the formation and or growth of pituitary metastases. This observed genomic instability will be of value in predicting the potential metastatic behavior of these aggressive pituitary tumors.
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PMID:H-ras mutations in human pituitary carcinoma metastases. 815 9

Recently, it has been suggested that abrogation of the wild type p53 protein function may alter the cellular response to DNA damaging agents, including ionizing radiation. This study was designed to compre the relative radiosensitivity and tumorigenicity of rat embryo fibroblast (REF) cell lines transfected with a mutant form of the p53 gene (plasmid MTp53pro193), alone, or in combination, with the H-ras (plasmid pEJ6.6) and HPV16-E7 (plasmid pJ4 omega 16.E7) oncogenes. Transfection of the mutant p53pro193 gene alone resulted in selected clones having increased radioresistance in culture which correlated with increased mutant p53 expression in these clones. However, the co-transfection of mutant p53 and H-ras genes or triple transfection of mutant p53, H-ras and E7 genes resulted in clones with high mutant p53 expression, significantly increased radioresistance and uniform tumorigenicity. There was no correlation between intrinsic radioresistance and spontaneous metastasis in the tumorigenic REF transfectant clones. Stepwise acquisition of radioresistance and an aggressive tumor cell phenotype is observed when the mutant p53 gene and HPV E7 co-operate with the ras oncogene in transfection assays, and can be correlated to increases in mutant p53 expression.
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PMID:Mutant p53 increases radioresistance in rat embryo fibroblasts simultaneously transfected with HPV16-E7 and/or activated H-ras. 818 46

Anaplastic large-cell lymphoma (ALCL) represents a morphologically distinct type of non-Hodgkin's lymphoma (NHL) characterized phenotypically by the expression of the CD30 antigen, a new member of the nerve growth factor gene family. The lymphoid origin of ALCL has been documented using immunohistochemical and molecular genetic analyses. However, very little is known so far regarding the precise pathogenetic mechanisms involved in its development and progression. Therefore, we investigated bcl-2, p53, and retinoblastoma gene (Rb) expression immunohistochemically; the occurrence of bcl-2, c-myc, and Rb gene rearrangements using Southern blotting; and the presence of ras and p53 gene somatic mutations by single-strand conformation polymorphism assay in a panel of 18 well-characterized ALCLs. In addition, the presence of Epstein-Barr (EBV) and human T-cell lymphotropic virus type I (HTLV-I) genomes were investigated using polymerase chain reaction. We identified abnormal c-myc gene products in 6 of 18 cases (33%) of ALCL. On the other hand, the bcl-2 and Rb genes were not rearranged and K-, N-, and H-ras gene somatic mutations were not found. Significant levels of p53 protein expression were found in more than 60% of ALCLs, but only a single ALCL carried a p53 gene mutation (exon 5). Only 3 ALCL cases, all occurring in human immunodeficiency virus-infected patients, were positive for EBV genomes. On the other hand, contrary to previous findings, no HTLV-I products could be identified. Despite the fact that the c-myc proto-oncogene appears to be frequently altered in ALCL, no pathognomonic abnormality could be identified and therefore additional studies and new strategies should be designed to identify the pathogenetic mechanisms involved in the development of ALCL.
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PMID:Molecular characterization of CD30+ anaplastic large-cell lymphoma: high frequency of c-myc proto-oncogene activation. 820 84

Desmoid tumors, which are locally invasive with recurrence but without metastasis, are frequently observed in patients with familial adenomatous polyposis after abdominal surgery or during pregnancy. This study analyzed mutation of the adenomatous polyposis coli gene in 8 desmoid tumors from 7 familial adenomatous polyposis patients using polymerase chain reaction-single-strand conformation polymorphism and the direct sequencing method. Seven somatic mutations, 1 somatic allele loss, and 6 germ-line mutations were detected. The majority of adenomatous polyposis coli gene mutations were deletions of 1 to 19 base pairs in exon 15, and all mutations led to the formation of stop codons. A somatic mutation with repetition of 82 base pairs from codon 1399 to 1426 was also observed in a desmoid, which was most likely caused by an error during replication or repair replication. No mutation was detected in exons 1 to 2 of H-ras, K-ras, and N-ras genes and in exons 5 to 8 of p53 gene, in these tumors. The simultaneous existence of somatic and germ-line alterations of adenomatous polyposis coli gene observed in all 8 tumors strongly suggests that inactivation of both alleles of adenomatous polyposis coli gene is involved in the development of desmoid tumors.
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PMID:Coexistence of somatic and germ-line mutations of APC gene in desmoid tumors from patients with familial adenomatous polyposis. 822 38

Chronic abuse of the analgesic drug phenacetin is associated with an increased risk of development of transitional cell carcinomas of the urinary tract. It is unclear whether phenacetin acts through chronic tissue damage (phenacetin nephropathy) or via a genotoxic metabolite causing promutagenic DNA lesions. In the present study, we investigated 15 urothelial carcinomas from 13 patients with evidence of phenacetin abuse. Tumors were screened for p53 mutations in exons 5-8 by single-strand conformation polymorphism (SSCP) analysis, followed by direct sequencing of PCR-amplified DNA. p53 Mutations were detected in 8/14 primary tumors (57%). All except one were missense mutations located in exon 5 (three mutations), exon 6 (one), exon 7 (two) and exon 8 (one). The type of mutation varied, with a preference for CpG sites. A frameshift mutation resulting from the insertion of a single cytosine at codons 151/152 was detected in a bladder tumor and its lung metastasis. Urothelial carcinomas located in the renal pelvis and in the ureter of the same patient exhibited two different mutations, strongly suggesting that they developed independently. Another patient had tumors in the renal pelvis and bladder, both of which contained the same p53 mutation, indicating intracavitary metastatic spread. This demonstrates that screening of p53 mutations allows the clonal origin of tumors in patients with multiple primary and metastatic lesions to be determined. None of the tumors investigated contained mutations in codons 12, 13 or 61 of H-ras or K-ras protooncogenes.
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PMID:p53 mutations in phenacetin-associated human urothelial carcinomas. 822 64

By manipulating the circulating blood level of androgen, it is possible to induce either the programmed death (apoptosis) or proliferation of prostatic glandular cells. To examine the role of differential gene regulation in these two procedure, the expression of the mRNA of a series of genes was quantitated on a per cell basis during the androgen ablation-induced programmed death of rat prostatic glandular cells. These results were then compared to quantitative analysis of the mRNA expression of these same series of genes during the proliferative regrowth of prostatic glandular cells induced in rats castrated for 1 week before being treated with exogenous androgen replacement. These comparisons demonstrated that androgen ablation-induced programmed death of prostatic glandular cells share several (i.e. c-myc, H-ras, and tissue transglutaminase), but not most, of the epigenetic changes associated with androgen-stimulated proliferation of these cells. No enhancement of the mRNA expression of several genes required for entrance of prostatic glandular cells into the S-phase of the proliferative cycle (i.e. histone-H4, c-fos, p53, and ornithine decarboxylase) occurred during androgen ablation-induced programmed death of these cells. These results demonstrated that neither entrance into the S-phase nor progression through a defective proliferative cell cycle is involved in androgen ablation-induced programmed death of prostatic glandular cells. This was further supported by the observation that there is a set of genes (i.e. TRPM-2, transforming growth factor-beta 1, alpha-prothymosin, and calmodulin) in which mRNA expression is only enhanced during programmed cell death and not during proliferation of prostatic glandular cells induced by androgen replacement. These results demonstrate that prostatic programmed cell death is a distinct pathway from cell proliferation involving differential gene regulation.
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PMID:Differential gene regulation during programmed death (apoptosis) versus proliferation of prostatic glandular cells induced by androgen manipulation. 824 89

In order to know the involvement of multiple gene alterations in the pathogenesis of human lung cancer, we examined the genes of K-, H-ras (codons 12, 13, 61), p53(exons 5-9) and the retinoblastoma susceptibility gene (RB)(exons 20-22) using the polymerase chain reaction/single-strand conformation polymorphism method in 32 human lung cancer cell lines (5 squamous-cell carcinomas, 10 adenocarcinomas, 3 large-cell carcinomas, 14 small-cell carcinomas). In 18 non-small-cell lung cancer lines, gene alterations were found in 4 for K-ras (22%), none for H-ras (0%), 4 for p53 (22%) and none for the RB (0%) gene. In 14 small-cell lung cancer (SCLC) lines, no gene alterations were found in K-ras (0%), or H-ras (0%), but 6 were found for p53 (43%) and 3 for the RB (21%) gene. Coincident abnormalities of K-ras and p53, or K-ras and RB genes were not found in any cell lines, and those of the p53 and RB genes were found in only 2 SCLC lines. No association was observed between these three gene alterations and N-myc amplification. Although the above three genes may be involved to some extent in the pathogenesis of lung cancer, more factors are required for its development.
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PMID:Gene analysis of K-, H-ras, p53, and retinoblastoma susceptibility genes in human lung cancer cell lines by the polymerase chain reaction/single-strand conformation polymorphism method. 826 9

The GTPases comprise a superfamily of GTP-binding proteins with intrinsic GTPase activity. Some members of this family representing either heterotrimeric or small G-proteins are involved in the transmission of mitogenic signals. Mutations that lead to constitutively activated G-proteins have been shown to contribute to malignant transformation. These genes represent, therefore, putative oncogenes. Examples are the gsp and gip2 oncogenes, encoding GTPase deficient alpha-subnits of Gs or Gi-2 proteins. Representatives from the family of small G-proteins are the products of the Harvey-, Kirsten- or N-ras oncogenes. These oncogenes, which are frequently expressed in human malignancies, code for proteins (p21ras) that are locked in the activated GTP-bound state because their GTPase is refractory to the ras-specific GTPase activating protein (GAP). In other cases p21ras-GTP levels have been found to be elevated as a result of an increase in GDP/GTP exchange rate. In neurofibromatosis v. Recklinghausen, a mutated gene (NF1) is detectable. The protein encoded by NF1 contains a GAP homology region, binds p21ras-GTP, and stimulates the hydrolysis of p21ras-bound GTP. Both ras-GAP (p120 GAP) and NF1-GAP are inhibited by acidic lipids. Elevated levels of these lipids may exert growth-stimulatory or perhaps tumor-promoting activity by increasing p21ras GTP. The function of transforming p21ras is under control of tumor suppressor genes. Putative suppressor genes isolated from revertants from ras-transformed cells include rsp-1 and the ras recision gene (rrg). Experimentally, an overexpression of Rap 1A/Krev-1 is able to antagonize transformation by p21ras. This mechanism also may be relevant under normal conditions. p53 also is capable of inhibiting transforming p21ras. It is postulated that p105-RB exerts a similar anti-ras effect. The mechanism by which retinoic acid suppresses transformation by ras is discussed. Current strategies for a pharmacological interference of p21ras function are described.
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PMID:Role of GTPases and GTPase regulatory proteins in oncogenesis. 835 39

In a previous study, the spectrum of H-ras mutations detected in B6C3F1 mouse liver tumors induced by 5, 50 or 150 mumol/kg body wt of N-nitrosodiethylamine (NDEA) was similar to that in spontaneous B6C3F1 mouse liver tumors, suggesting that activation of the H-ras gene in NDEA-induced mouse liver tumors may not be the direct result of the chemical interaction with the H-ras gene. In the present study, mutations in the H-ras oncogene from B6C3F1 mouse liver tumors induced by 5 or 50 mumol/kg body wt of NDEA were characterized by DNA amplification with polymerase chain reaction (PCR), single-strand conformation of polymorphism (SSCP) and direct sequence analysis. Twenty-one of 66 NDEA-induced B6C3F1 mouse liver tumors contained activated H-ras gene with 2 of 21 having a CG to AT transversion at the first base of codon 61, 17 of 21 having AT to GC transition and 2 of 21 having an AT to TA transversion at the second base of codon 61 in the H-ras gene. The predominant mutation, AT to GC transition (17/21, 81%) is consistent with the formation of O4-ethylthymine adduct, and is distinct from the predominant CG to AT transversion (50%) at the first base of codon 61 detected in H-ras gene from NDEA-induced B6C3F1 mouse liver tumors in a previous study by Stowers et al. Mutations in the K-ras oncogene from 59 A/J mouse lung tumors induced by 0.53 mmol/kg body wt of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were also characterized by using the above mentioned methods. Forty-six of 59 NNK-induced A/J mouse lung tumors contained activated K-ras genes. All 46 (100%) of the activated K-ras gene had GC to AT transitions at the second base of codon 12. The same mutation was observed in 70% (7/10) of the K-ras oncogene from A/J lung tumors induced by 4.8 mmol/kg body wt (given in 21 doses) of NNK. These data suggest that other factors in addition to genotoxic effect might be involved in the induction of rodent tumors by some carcinogens when given at higher doses. Therefore, further studies to compare the dose-dependent differences in the profile of ras mutations induced by chemical carcinogens may help to assess human cancer risk. Mutation(s) in exons 5-8 of the p53 gene was not found in these NDEA-induced mouse liver tumors and NNK-induced mouse lung tumors.
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PMID:Dose-dependent ras mutation spectra in N-nitrosodiethylamine induced mouse liver tumors and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced mouse lung tumors. 835 44

The availability of p53 knockout mice generated by gene targeting has enabled us to investigate the functional role of the p53 tumor suppressor gene in initiation, promotion, and progression of carcinogenesis in vivo, using mouse skin as a model system. The number, size, and growth rate of benign papillomas were not increased in the p53 heterozygous mice in comparison with wild type. The p53 null mice showed a reduced yield of papillomas, but these underwent much more rapid malignant progression, with some poorly differentiated carcinomas developing after only 10 weeks of promotion. Progression rate was also greater in heterozygous than in wild-type mice and was associated with loss of the remaining wild-type allele. Most tumors from all groups had activating mutations in the H-ras gene. Absence of p53, therefore, does not augment the frequency of initiation or the rate of promotion but greatly enhances malignant progression.
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PMID:Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. 837 52


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