Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Point mutations in codons 12, 13 or 61 of the oncogenes Ha-ras, Ki-ras or N-ras have been identified in human malignancies of many types. Using the PCR (polymerase chain reaction) technique for DNA amplification in vitro and stringent probing of the amplified DNA on dot blots with a library of specific oligonucleotides, we have screened for the presence of ras mutations in oral and para-oral malignancies and some associated lesions. The material, from UK patients, consisted of 22 oral squamous-cell carcinomas including 5 neck metastases, 1 oral mucosal dysplasia, 1 proliferative verrucous leukoplakia, 1 antral and 1 tonsillar carcinoma, 1 basal-cell carcinoma, 1 salivary adenocarcinoma, 1 salivary adenoid cystic carcinoma and 1 lung adenocarcinoma metastatic to the gingiva. Genomic DNA was extracted from tissues which were fresh or preserved in liquid nitrogen. Two DNA samples contained point mutations in codon 61 of Ki-ras. One of these mutations was in the lymphocytes infiltrating a retromolar SCC. The other mutation (CAA to CAU; substitution of glutamine by histidine) was in the lung adenocarcinoma metastasis. The absence of ras mutations in the epithelium of primary oral squamous-cell carcinomas is of considerable interest as other work in our Department on Indian cases of oral carcinomas associated with chewing tobacco (quid) revealed that 35% of these had a codon 12, 13 or 61 mutation in Ha-ras. While ras activations arising from point mutations may occur in a high proportion of oral malignancies associated with chewing tobacco (quid), this was not the case in UK oral malignancies, even where tobacco was smoked.
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PMID:Ras mutations in United Kingdom examples of oral malignancies are infrequent. 204 May 36

Male F344 rats were fed 0.2% N-[4-(5-nitro-2-furyl)-2-thiazoly]formamide for 6 weeks and then fed 3% or 5% sodium saccharin, 5% sodium ascorbate, 3.12% calcium saccharin, 1.34% sodium chloride, 5.2% calcium saccharin plus 1.34% sodium chloride, or basal diet alone for 72 weeks. Protein and DNA were extracted from 89 bladder tumors [87 transitional cell carcinomas (TCC), 1 papilloma, and 1 sarcoma] from 86 rats p21 expression was examined by Western blotting using a monoclonal antibody against p21 (NCC-RAS-004). H-ras mutations in exons 1 and 2 were examined by direct sequencing of DNA amplified by polymerase chain reaction. Sequencing results demonstrated mutations at codon 61 (CAA to CGA in 15 TCCs; CAA to CTA in 2 TCCs), at codon 12 (GGA to TGG in 1 TCC), and at codon 13 (GGC to GTC in 3 TCCs). Mutations at codon 61 were confirmed by faster mobility of the p21 band in Western blots. The level of p21 expression varied among samples, but many TCCs appeared to express more p21 than controls. The overall incidence of H-ras mutations was 24.4% (21 of 86 rats). The type of chemical used for the promoting phase had essentially no effect on H-ras mutation, suggesting that the effects observed were related to FANFT administration. The frequency of H-ras mutation in each group was negatively related to the incidence of carcinoma (r = -0.85; P less than 0.01). Two groups of tumors (with or without the mutated ras gene) were compared for tumor size (reflected by the bladder weight), histological grading, and the presence of invasion. The size of tumors with mutated ras was significantly smaller than those without mutated ras. There was no difference in the histological grading between the two groups. Although not statistically significant, histological invasion was more frequently observed in tumors with mutated ras (14.3%) than in tumors without mutation (3.1%).
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PMID:H-ras mutations in rat urinary bladder carcinomas induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide and sodium saccharin, sodium ascorbate, or related salts. 205 86

Male F344 rats were fed N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) for up to 4 wk, then were given the basal diets (Prolab 3200 or AIN-76A) with or without 5% sodium saccharin for up to 100 wk. Eleven transitional cell carcinomas (TCCs), one undifferentiated carcinoma, and two sarcomas of the urinary bladder were examined for the expression of ras gene product, p21, by immunohistochemical staining and western blot analysis. Point mutation in codons 12 or 61 of the Ha-ras genes amplified by polymerase chain reaction was examined by a slot-blot screening procedure using allele-specific oligonucleotide probes. Immunohistochemical staining showed enhanced immunoreactivity with the antibody to ras p21 in seven TCCs and one undifferentiated carcinoma. Western blot analysis showed faster migration of the p21 band in 6 of 11 TCCs. Oligonucleotide hybridization revealed the point mutation in codon 12 of Ha-ras gene (GGA----GTA in 1 TCC) and in codon 61 (CAA----CGA in 5 TCCs and CAA----CTA in 1 TCC). Two mutations in codons 12 and 61 coexisted in one tumor, which were found to be present in different Ha-ras alleles. The incidence of Ha-ras gene mutations were similar in groups treated with (3 of 6) or without (3 of 8) sodium saccharin. These results suggest the involvement of activated Ha-ras gene in rat urinary bladder carcinogenesis induced by FANFT.
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PMID:Point mutation in codons 12 and 61 of the Ha-ras gene in rat urinary bladder carcinomas induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide. 220 84

Activated N-ras gene was isolated from human hepatoma tissue by DNA transfection assay coupled with the neomycin selection method and molecular cloning and a point mutation in the codon 61 (CAA----AAA) was noted. However, examination of the proportion of the mutated N-ras gene in the tumor part by molecular cloning and by hybridization using synthetic oligonucleotide probes indicated that the mutated gene occurred with very low frequency. The activated N-ras gene appears located only in a small fraction of the tumor cells. The experimental data indicate activation of this gene as possibly not the major cause of carcinoma, but rather a manifestation of tumor heterogeneity.
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PMID:Activated N-ras gene was found in human hepatoma tissue but only in a small fraction of the tumor cells. 253 92

Apolipoprotein (apo) B mRNA undergoes a novel tissue-specific editing reaction, which replaces a genomically templated cytidine with uridine. This substitution converts codon 2153 from glutamine (CAA) in apo B100 mRNA to a stop codon (UAA) in apoB48 mRNA (Powell, L. M., Wallis, S. C., Pease, R. J., Edwards, Y. H., Knott, T. J., and Scott, J. (1987) Cell 50, 831-840). To examine sequences in the human apoB mRNA required for the editing reaction, a series of deletion mutants around the cytidine conversion site was prepared and transfected into a rat hepatoma cell line (McArdle 7777). This cell makes both apoB100 and apoB48. Editing was detected by a primer extension assay on cDNA that had been amplified by the polymerase chain reaction. RNAs of between 2385 and 26 nucleotides spanning the conversion site underwent similar levels of conversion. Editing was confirmed by cloning and sequencing of cDNA corresponding to the transfected RNAs. Conversion did not occur in transfected human hepatoblastoma (HepG2) or epithelial carcinoma (HeLa) cell lines, which do not make apoB48. These results verify that apoB48 is generated by a genuine tissue-specific RNA editing reaction and show that 26 nucleotides of apoB mRNA are sufficient for editing.
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PMID:Sequence requirements for apolipoprotein B RNA editing in transfected rat hepatoma cells. 276 26

Dichloroacetic (DCA) and trichloroacetic (TCA) acids, two major by-products formed during chlorine disinfection of drinking water, increase the incidence of tumors in B6C3F1 mice by 6- and 3-fold respectively. In order to understand better the mechanism by which these two compounds induce liver tumors, the incidence and spectrum of mutations in the K- and H-ras proto-oncogenes in these tumors were analyzed. DNA from spontaneous, DCA- and TCA-induced liver tumor from B6C3F1 male mice was evaluated for point mutations in exons 1, 2 and 3 of the two genes by single-stranded conformation polymorphism. Results demonstrated a similar incidence of mutations for exon 2 of H-ras in spontaneous carcinomas (58%), and in carcinomas induced by DCA 3.5 g/l (50%), 1.0 g/l (48%) and TCA 4.5 g/l (45%). Only four showed mutations in the other exons of Hras or in K-ras. Sequence analysis of spontaneous tumor samples with second exon H-ras mutations revealed a change in codon 61 from CAA to AAA in 80% and CAA to CGA in 20% of tumors. In contrast, tumors with H-ras mutations from DCA-treated mice revealed a H-61 change from CAA to AAA in 21% at 3.5 g/l and 16% at 1.0 g/l. CAA to CGA was observed in 50% of tumors from mice given DCA 3.5 or 1.0 g/l, and CAA to CTA was present in 29% and 34% of the two dosage groups respectively. Interestingly, TCA showed the same mutational spectrum as the spontaneous liver tumors. The data indicates that induction of liver carcinoma by DCA and TCA involves activation of the H-ras proto-oncogene at a frequency similar to that observed in spontaneous tumors. However, the mechanism(s) for including hepatocellular carcinoma does not appear to be identical for DCA and TCA.
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PMID:Ras oncogene activation during hepatocarcinogenesis in B6C3F1 male mice by dichloroacetic and trichloroacetic acids. 769 4

Using the method of polymerase chain reaction-single strand conformation polymorphism, the point mutations of the ras oncogenes in a total of 33 thyroid tissues, including 12 follicular adenomas, 6 follicular carcinomas, 11 papillary carcinomas, and 4 undifferentiated carcinomas, were examined. The frequency of the mutation was 3% (1/33) in codon 12, 13 of Ki-ras and 18% (6/33) in codon 61 of N-ras, including 17% (2/12) in follicular adenoma, 50% (3/6) in follicular carcinoma, 0% (0/11) in papillary carcinoma and 25% (1/4) in undifferentiated carcinoma. In follicular adenoma, positivity was observed in microfollicular or trabecular subtypes. Furthermore, the mutation of ras, was examined in histologically different parts, coexisting in the same tumor in a total of four cases. Both the undifferentiated carcinoma and coexisting follicular adenoma, and both the microfollicular adenoma and trabecular nodule growing in the tumor, had the same N-ras (61) mutation. Direct sequencing analysis showed that all mutations were CAA (Gln) to CGA (Arg) transition of codon 61, except for CAA to AAA transversion in one case of follicular carcinoma. A similar genetic abnormality of N-ras genes at codon 61 between follicular adenoma and follicular carcinoma suggests that the mutation of N-ras at codon 61 might play a part in oncogenesis in follicular tumors.
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PMID:N-ras mutation of thyroid tumor with special reference to the follicular type. 770 43

Male F344 rats were fed N[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) for up to 4 wk, then given the basal diet with or without 5% sodium saccharin for up to 100 wk. In a previous study, we demonstrated point mutations in codons 12 and 61 of Ha-ras gene among eleven transitional cell carcinomas (TCC), one undifferentiated carcinoma, and two sarcomas of the urinary bladder (Mol Carcinogen 3:210-215, 1990). In this study, Ha-ras, Ki-ras, and N-ras sequences were examined by polymerase chain reaction (PCR) and direct DNA sequencing. The results confirm the point mutation in codon 61 (CAA to CGA in 5 TCCs and to CTA in one TCC) of the Ha-ras gene. Mutation at codon 12 was not confirmed. No mutation was found in the Ki-ras gene. Sequences of the N-ras gene exons 1 and 2 were determined, and no mutations was detected. These results suggest the involvement of activated Ha-ras gene, but not Ki-N or N-ras gene, in rat urinary bladder carcinogenesis induced by FANFT. Subsequent sodium saccharin administration did not affect the changes in Ha-ras gene.
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PMID:Sequencing analysis of Ha-, Ki-, and N-ras genes in rat urinary bladder tumors induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and sodium saccharin. 790 76

Direct sequencing using Taq enzyme was established for determination of point mutation of K-ras gene at codon 12 in 9 wax samples of pancreatic carcinoma (PC) and 1 of islet cell tumor. Point mutation occurred in 5 of 9 samples of PC and manifested two types of mutation, CCA-->CGA in 4 and CCA-->CAA in 1. The changes of amino acid included changes of glycine to alanine and glycine to valine. The causes of mutation frequency and the content differed from that of foreign reports were analysed in addition to the significance of determining point mutation of K-ras gene at codon 12.
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PMID:[Point mutation of K-ras gene in pancreatic carcinoma]. 806 25

Three series of biopsy specimens of premalignant and malignant oral lesions, together with seven human keratinocyte cultures, previously established from oral squamous cell carcinomas, were analysed for point mutation in exons 1 and 2 of the c-Ha-ras, c-Ki-ras and N-ras genes by direct nucleotide sequencing of DNAs amplified in the polymerase chain reaction (PCR). Only one out of 12 biopsy samples (8.3%), a well-differentiated carcinoma which was the latest in a series of floor of mouth lesions from 1 of the 3 patients studied, harboured a mutant c-Ha-ras gene, being heterozygous at codon 12 for a GGA-GTA change. One cell line (H357) showed heterozygosity in both exons 1 and 2 of c-Ha-ras, harbouring a GGT to AGT mutation over codon 13 and a CAG to CAA mutation over codon 61. The remaining six oral carcinoma cell lines (85.7%) were homozygous normal at both exons 1 and 2 of c-Ha-ras. All cell lines showed normal c-Ki-ras and N-ras loci. We conclude that ras gene mutation is an infrequent occurrence in the malignant progression of oral epithelial cells, despite the probable importance of chemical carcinogens in the aetiology of the disease. We emphasise the need to search for other cellular sequences which may be targets for chemical or viral carcinogens.
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PMID:Ras gene point mutation is a rare event in premalignant tissues and malignant cells and tissues from oral mucosal lesions. 818 May 79


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