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)

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

The incidence and pattern of mutations of the ras oncogenes and the p53 tumor suppressor gene have been shown to differ among different cancer types and even among the same cancer types with different etiological backgrounds. For example, in a previous study we showed that not only the etiology but also the incidence of point mutation of the c-Ki-ras oncogene in cholangiocellular carcinomas (CCCs) differ between Japanese and Thai patients. In the study presented here, we examined the incidence of mutations in the ras gene family and the p53 gene in CCCs of both Japanese and Thai patients by single-strand conformation polymorphism and direct sequencing analyses and compared the pattern of p53 mutation between these two CCC groups. Although the incidence of ras mutation differed markedly between Japanese (seven of 12, 58%) and Thai (two of 26, 8%) cases, the incidence of p53 mutation was similar: four of 12 (33%) and nine of 26 (35%), respectively. Except for one case in which deletion-insertion was detected in the second exon of the N-ras gene, all ras mutations occurred at codon 12 or 13 of the c-Ki-ras gene. All p53 mutations but one were detected in a highly conserved region, and the predominant form of the mutations was G:C-->A:T transition at CpG sites in both Japanese and Thai cases, similar to that reported for colorectal cancers. Therefore, in contrast to the ras oncogenes, mutation of the p53 gene was frequently involved in the development of CCCs in both Japanese and Thai patients, irrespective of any difference in etiology.
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PMID:Mutations of the p53 tumor suppressor gene and the ras gene family in intrahepatic cholangiocellular carcinomas in Japan and Thailand. 828 Mar 80

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

We previously reported (T. Enomoto et al., Cancer Res., 50: 6139-6145, 1990; T. Enomoto et al., Cancer Res., 51: 5308-5314, 1991) a significant frequency of activating point mutations in codon 12 of the c-K-ras-2 protooncogene in endometrial adenocarcinoma and its premalignant precursor lesions (series 1 and 2). To reveal the role of the p53 tumor suppressor gene in the development of endometrial adenocarcinoma and to study the association of p53 alterations with K-ras activation, an additional 28 endometrial adenocarcinomas and an additional 11 premalignant atypical uterine hyperplasias (series 3), as well as 12 cases of endometrial adenocarcinoma (10 having K- or N-ras activation) and 2 cases of atypical hyperplasia from series 1 and 2, were screened for the presence of p53 alterations. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 6 of 19 (32%) informative cases of endometrial adenocarcinoma and 1 of 4 (25%) informative cases of endometrial atypical hyperplasia by restriction fragment length polymorphism analysis and by single-strand conformation polymorphism analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by single-strand conformation polymorphism analysis of PCR-amplified DNA fragments. Mutations were found in 9 of 40 (23%) endometrial adenocarcinomas and 1 of 13 (8%) atypical hyperplasias that were studied. Mutations in p53 were significantly more frequently found in clinical grade 3 (G3) cancers (6 of 14, 43%) than in G1-G2 cancers (3 of 26, 12%) (P = 0.033). Mutations were subsequently confirmed by direct sequencing. Single missense base substitutions were detected in 6 cases of endometrial carcinoma and in one case of atypical hyperplasia. Deletions of a single base and of 2 bases were each detected in single cases of endometrial carcinoma, and a single base insertion was found in a third case. Point mutations in K-ras were also identified in tumors of series 3 by direct sequencing of PCR-amplified DNA fragments of exons 1 and 2. Point mutations in codons 12 and 13 in K-ras were detected by direct sequencing of PCR-amplified DNA in 7 of 28 adenocarcinomas in series 3, but none were found in exon 2 (codons 59.63. The spectrum of point mutations in p53 in endometrial adenocarcinomas was almost identical to what we found in K-ras in series 1 and 2 and in series 3, suggesting the possible role of a mutagen that might be responsible for mutations in both K-ras and p53.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations of the p53 tumor suppressor gene and its association with activation of the c-K-ras-2 protooncogene in premalignant and malignant lesions of the human uterine endometrium. 838 72

A G:C-->T:A mutational hotspot at codon 249 of the p53 tumor suppressor gene has previously been identified in hepatocellular carcinoma (HCC) of patients from Qidong, China and southern Africa in which aflatoxin B1 (AFB1) and hepatitis B virus (HBV) are known synergistic risk factors. We have examined p53 mutation patterns of HCC from geographic areas in which the risk factors vary. Nine HCC lines and four hepatoblastoma lines (HB) were examined for p53 gene mutations and the relationship with HBV infection. Five of the nine HCC lines had homozygous mutation or deletion randomly distributed in exons 6-8, whereas none of the four HB cell lines had p53 mutations. One of the four HB lines (HepG2) had an N-ras mutation at codon 61 position 2. The p53 point mutations in the three HCC cell lines from Japan resulted in the amino acid changes of cysteine for tyrosine in cell line HuH 7 at codon 220 (A:T-->G:C), alanine for glycine in cell line HLF at codon 244 (G:C-->C:G), and serine for arginine in cell line HLE at codon 249 (G:C-->C:G). In addition, the deletion of 18 base pairs from codon 264 position 3 to codon 270 position 1 has resulted in the deletion of Leu-Gly-Arg-Asn-Ser-Phe from the amino acids sequences 256-270 in the Japanese cell line HuH 4. The cell line PLC/PRF/5 that showed p53 mutation at codon 249 (G:C-->T:A) with substitution of serine for arginine was derived from a South African patient. Our results indicate that whereas the p53 gene is not mutated in the HB cell lines, the HCC cell lines frequently contain an abnormal p53 gene. In addition, p53 point mutations were not detected in the four Japanese HCC cell lines that were positive for genomic integration of HBV X-gene and surface antigen gene. The three Japanese HCC cell lines with p53 mutations did not contain HBV sequences, indicating that hepatocarcinogenesis associated with p53 mutation does not require the genomic integration of HBV sequences.
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PMID:p53 gene mutation and integrated hepatitis B viral DNA sequences in human liver cancer cell lines. 838 56

The p53 gene is currently thought to be a tumor suppressor gene, and its alterations have been suggested to be involved in the pathogenesis of several human malignancies, including some leukemias and lymphomas. We present here evidence for the possible involvement of p53 gene mutations in the myelodysplastic syndrome (MDS), although the incidence is relatively low. Forty-four patients with MDS and six patients with overt leukemias that developed from MDS were studied for p53 gene alterations using reverse transcriptase-polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequencing. Three patients with MDS (2 RAEB and 1 RAEB in T) had missense point mutations in the conserved regions of the p53 coding sequence. Furthermore, expression of the wild-type p53 mRNA was not detected in these three patients. The probable absence of normal p53 function in the three cases studied here suggests that alterations in the p53 gene may occasionally play a role in MDS. These three MDS patients with p53 gene mutations and an MDS-derived erythroleukemia cell line that we had previously reported to carry a p53 gene mutation showed no N-ras gene mutations, suggesting heterogeneity in the oncogenic mechanism of MDS.
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PMID:Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. 849 37

Non-familial human adrenocortical adenomas and carcinomas were screened for mutations in exons 5-8 of the p53 tumor suppressor gene by single-strand-conformation-polymorphism (SSCP) analysis, followed by direct sequencing of PCR-amplified DNA. Point mutations in codons 12, 13 and 61 in H-ras, K-ras and N-ras proto-oncogenes were similarly assessed by direct DNA sequencing. Three out of 15 primary adrenocortical carcinomas (20%) contained a mis-sense point mutation in the conserved regions (exons 5 and 8) of the p53 gene. Mutations were located in codon 157 (GTC-->TTC; Val-->Phe), codon 163 (TAC-->AAC; Tyr-->Asn), and codon 273 (CGT-->TGT; Arg-->Cys). The mutation in codon 157 was detected in the primary tumor as well as in brain and lymph-node metastases. Among 18 adrenocortical adenomas, there was only a single non-miscoding mutation in codon 295 (CCT-->CCC; Pro-->Pro). These data suggest that mutational inactivation of the p53 gene occurs in a minority (20%) of sporadic adrenocortical carcinomas and that these mutations constitute a late event in the multi-step process of malignant transformation. No ras mutations were detected in any of these tumors, suggesting that these genes are not involved in the development of tumors originating from the adrenal cortex.
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PMID:p53 mutations in sporadic adrenocortical tumors. 850 16

The alkylating agent 4-nitroquinoline 1-oxide (4-NQO) is a powerful carcinogen and induces squamous cell hyperplasia, squamous cell dysplasia, papilloma, and squamous cell carcinoma (SCC) in rat oral epithelia. Oral cancers induced by a single application of 4-NQO develop through a multistage process in a way similar to the development of this cancer in humans. In this study, mutations in exons 1 and 2 of Ki-ras, N-ras, and Ha-ras and exons 4-7 of p53 were examined by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis, followed by PCR-direct sequencing for the confirmation of mutations. Samples for the mutation analysis were obtained from dysplasias, papillomas, and SCCs on the tongue epithelia induced in F344 rats by adding 4-NQO (20 ppm) to their drinking water for 8 wk. The Ha-ras mutations (61A-->T transversions in the second position) were found in five of 29 (17%) samples (one dysplasia and four SCCs). However, no mutations were detected in either Ki-ras, N-ras, or p53 under two different conditions of PCR-SSCP analysis. We suggest that some neoplasms in oral carcinogenesis induced by 4-NQO may involve Ha-ras mutations but not mutations in Ki-ras, N-ras, or p53. The 4-NQO-induced rat oral carcinogenesis model may provide a system for evaluation of the mechanisms of multistage oral carcinogenesis associated with Ha-ras mutation without Ki-ras, N-ras, or p53 mutation.
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PMID:Infrequent Ha-ras mutations and absence of Ki-ras, N-ras, and p53 mutations in 4-nitroquinoline 1-oxide-induced rat oral lesions. 851 19

Carcinogenesis is a multigenic phenomenon where 3 prevailing types of genes are involved: oncogenes which stimulate the cell proliferation, tumor suppressor genes which act as inhibitors and metastagenes which contribute to the tumor progress. In animal models it has been shown that epithelial skin carcinogenesis proceeds stepwise: initiation, promotion, premalignant progression and finally malignant conversion. The oncogene c-H-ras and the tumor suppressor gene P53 are the genes whose involvement in these steps of epithelial skin cancers are duly established. Less experimental data are available concerning melanoma. the role of the oncogene N-ras, the tumor suppressor gene MTS-1 (encoding for protein p16) ans the metastagene nm 23 has recently be emphasized. Some cytogenetic abnormalities on chromosomes 1, 6, 9, 10, 11 and 17 have also been observed and incite to look for other genes potentially involved in the development of this tumor.
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PMID:[Genetic bases of cutaneous tumors]. 852 16

The ability of ras oncogenes and mutant p53 to activate reporter gene expression from human and rodent mdr1 gene promoters was described, although functional significance of this finding was unclear. We analyzed the influence of various forms of recombinant human ras and p53 on the mdr1 gene expression and P-glycoprotein (Pgp) function in rodent immortalized fibroblasts. The ras genes, in addition to activation of exogenous human mdr1 gene promoter, caused an increase in (i) expression of endogenous mdr1 mRNA, (ii) Pgp activity as determined by flow cytometry analysis of Rhodamine 123 exclusion, and (iii) resistance of cells to the cytotoxic action of colchicine and some other drugs. To elucidate whether the same signalling pathway is responsible for multidrug resistance induced by various oncogenes and protein kinase C (PKC), we tested the effects of v-mos and the PKC agonist 12-O-tetradecanoylphorbol-13-acetate. Similarly to cells transformed by ras, a Rat1 subline transformed by the v-mos oncogene was characterized by decreased drug sensitivity. On the contrary, Rat1 cells treated with the protein kinase C agonist 12-O-tetradecanoylphorbol-13-acetate showed neither increased mdr1 mRNA expression nor stimulation of Pgp function. Introduction by retrovirus-mediated gene transfer of wild-type p53 into Rat1 cells or into murine p53-deficient 10(1) and 10(3) cells did not change the Pgp function significantly, whereas in Rat1 cells transformed by activated N-ras or v-mos, expression of wild-type p53 caused partial reversion of oncogene-induced drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of exogenous ras and p53 on P-glycoprotein function in immortalized rodent fibroblasts. 852 64


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