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

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

Isolated amyloidomas may, albeit rarely, involve the central nervous system. There are three previous reports of amyloidomas that involved the gasserian ganglion and caused unilateral trigeminal neuropathies. The authors report the case of a 49-year-old woman with apparently isolated amyloidomas that caused slowly progressive bilateral trigeminal neuropathies. Magnetic resonance imaging of the brain revealed mild swelling of the left trigeminal nerve within the cavernous sinus and uniform enhancement with gadolinium throughout the length of the nerve. At craniotomy, the trigeminal nerve and ganglion were observed to be infiltrated by a tumor-like mass. Biopsy showed extensive infiltration of the nerve and ganglion by amyloid. Immunocytochemical studies of the amyloid were negative for immunoglobulins, kappa and lambda light chains, beta-amyloid A4 protein, transthyretin, beta 2-microglobulin, cystatin C, and gelsolin, but weak focal immunoreactivity with antiamyloid AA antibody was seen in the amyloid in vessels and in some intraneural deposits. Extensive investigations failed to reveal evidence of either systemic amyloidoses or an underlying inflammatory disorder or malignancy.
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PMID:Bilateral trigeminal amyloidoma: an unusual case of trigeminal neuropathy with a review of the literature. Case report. 793 26

Racemic anti-benzo[c]phenanthrene-3,4-diol-1,2-epoxide (anti-B[c]PhDE) is a powerful rat mammary carcinogen and is one of the most potent diol-epoxide tumorigens in mouse skin. Activation of ras genes has been proposed to be involved in tumorigenesis by this and related polynuclear aromatic hydrocarbon metabolites. Therefore, we analyzed rat mammary tumors and mouse skin tumors induced by anti-B[c]PhDE for mutations at codons 12, 13 and 61 of the Ki-ras and Ha-ras genes. No Ki-ras mutations were detected in either tumor type. In the rat mammary tumors, no Ha-ras mutations in codons 12 or 13 were observed in 25 tumors analyzed. Only one, a CAA-->CTA mutation, was detected in codon 61, of 42 tumors analyzed. These results indicate that Ki-ras and Ha-ras mutations are not involved in the induction of rat mammary tumors by anti-B[c]PhDE. Mutations in codon 61 of the Ha-ras gene were common, however, in mouse skin tumors induced by this diol-epoxide, being detected in 63% of the tumors analyzed; 90% of these mutations were CAA-->CTA. A dose-dependent difference in the occurrence of the CAA-->CTA mutations was observed; they were present in 75% of the tumors induced by a 100 nmol initiating dose of the diol-epoxide, but in only 34.5% of the tumors induced by a 400 nmol initiating dose. A CAA-->CTA mutation in codon 61 of Ha-ras was also detected in one of four acetone control tumors. In comparison with previous studies of other polynuclear aromatic hydrocarbons and their metabolites, the results suggest that the reactivity with DNA of anti-B[c]PhDE is one factor involved in the induction of A mutations in Ha-ras genes in mouse skin, but further studies are required to evaluate the significance of these mutations in mouse skin tumorigenesis.
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PMID:Contrasting incidence of ras mutations in rat mammary and mouse skin tumors induced by anti-benzo[c]phenanthrene-3,4-diol-1,2-epoxide. 795 41

Treatment of B6C3F1 mice with concentrations of 62.5-625 p.p.m. 1,3-butadiene by inhalation for up to 2 years causes a significantly increased incidence of Harderian gland (HG) neoplasms over untreated controls (Melnick,R., Huff,J., Chou,B.J. and Miller,R.A. Cancer Res., 50, 6592-6599, 1990). Since a specific K-ras mutation (codon 13 GGC-->CGC) had previously been described in lung and liver tumors from 1,3-butadiene-treated B6C3F1 mice, we analyzed 23 adenomas and six adenocarcinomas of the HG from mice exposed to 1,3-butadiene for this mutation and mutations in the H-ras gene. We also examined ras activation in 16 spontaneously occurring HG adenomas and one adenocarcinoma. DNA samples were prepared from paraffin-embedded tissues and analyzed by PCR followed by direct sequencing methods. Only one 1,3-butadiene-induced HG tumor contained the K-ras codon 13 mutation previously detected in lung and liver tumors. However, 16/29 HG tumors from the treated B6C3F1 mice contained H-ras codon 61 mutations. The mutations detected were: 12 CAA-->CGA transitions, two CAA-->CTA and two CAA-->AAA transversions. Eleven of 17 spontaneous HG tumors contained mutations in H-ras codon 61: five CAA-->CGA transitions, two CAA-->CTA transversions and four CAA-->AAA transversions. While the spectrum of ras mutations did not differ between the spontaneously occurring and chemically induced tumors, these data indicate that activation of H-ras contributes to the process of HG tumorigenesis in both groups of these neoplasms.
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PMID:Activation of H-ras is prevalent in 1,3-butadiene-induced and spontaneously occurring murine Harderian gland tumors. 795 23

We investigated the appearance and activity of the cysteine proteinase cathepsin B and its physiological inhibitors, stefins A and B, at the cellular level in human tumor cell lines HS-24, derived from a primary lung tumor (squamous cell), and SB-3, derived from a metastasis (lung adenocarcinoma). In addition to cathepsin B, these tumor cells also expressed the immunologically and functionally related cathepsin L, but not cathepsin H. Stefin A was found in HS-24 but not in SB-3 cells; stefin B was found in both cell types. Using a specific fluorogenic cytochemical assay, the intracellular activity of the enzyme was localized and quantified. Thus, the cellular cathepsin B kinetics for the synthetic substrates Z-Arg-Arg-4M beta NA and Z-Val-Lys-Lys-Arg-4M beta NA, its pH dependence and inhibition by E64, stefins A and B, and cystatin C could be determined. From these measurements it appeared that the enzyme exhibited different cleavage rates for these substrates in the different cell types, showed considerable cleavage activity at neutral pH, which was stable under these conditions for extended time periods, and was highly sensitive to the inhibitors E64 and cystatin C but was considerably less sensitive to stefins, particularly stefin A. By conventional light microscopy, confocal laser scanning microscopy, and electron microscopy the enzymatic activity was localized in lysosomes, as expected, but also in the endoplasmic reticulum, nuclear membrane, and plasma membrane. The endoplasmic reticulum is a site at which only pre-mature enzyme forms exist, which are usually not active. The appearance of enzymatic activity at the plasma membrane confirms earlier biochemical and immunofluorescence microscopic investigations. The different sites of localization within the cells make it likely that different forms of the enzyme are expressed simultaneously, which follow alternate ways of processing and sorting. Taken together, the results support an involvement of the enzyme under extracellular conditions in degradative processes.
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PMID:Cathepsin B activity in human lung tumor cell lines: ultrastructural localization, pH sensitivity, and inhibitor status at the cellular level. 801 75

Mutations in ras oncogenes were detected in cultured cells of mouse skin tumors induced by near-UV irradiation. DNA extracted from the UV-induced tumor cells was transfected to golden hamster embryo cells, and focus-forming ability was confirmed in 22 of 26 cell strains, 15 of which had the repetitive mouse sequence. Mouse ras genes were detected in 10 of these 22 cell strains. Point mutations in the ras genes were at Ha-ras codon 13 (GGC-->GTC in two strains, GGC-->AGC in one strain), Ki-ras codon 61 (CAA-->GAA in two strains), and N-ras codon 61 (CAA-->CAT in two strains, CAA-->AAA in two strains). In one tumor cell strain no base change was directed. Most mutations occurred at dipyrimidine sites. Pyrimidine dimers or pyrimidine(6-4)pyrimidone photoproducts are the likely cause of the skin cancers. The base change occurred preferentially at G.C base pairs, and transversions predominated.
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PMID:Mutations in ras genes in cells cultured from mouse skin tumors induced by ultraviolet irradiation. 804 67

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

A rapid and sensitive assay was developed to detect CAA-->AAA mutations at codon 61 of Ha-ras. The region surrounding codon 61 was amplified by the polymerase chain reaction (PCR) using one primer containing a mismatch at the second position of codon 60. Using this primer creates an Msel restriction enzyme site if codon 61 carries the C.G-->A.T transversion. An aliquot of the second PCR primer was 5'-end-labeled with 32P to increase the sensitivity of detection of the PCR product. After cleavage with Msel, DNA was electrophoresed on a nondenaturing polyacrylamide gel, and the products were visualized by autoradiography. The sensitivity of this assay was such that the mutation could be detected when present in only one of 200 alleles. DNA samples from spontaneous Crl:CD-1(ICR)BR mouse liver tumors were analyzed using this method. Nine of 38 samples contained the mutation, and in one of those nine, the mutation had not been previously detected by either direct sequencing of tumor DNA or by sequencing the DNA from NIH 3T3 cells transfected with the tumor DNA.
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PMID:A sensitive restriction fragment length polymorphism method to detect CAA-->AAA mutations at codon 61 of Ha-ras. 810 30

The lysosomal cysteine proteinase cathepsin B is shown to be secreted by ten human colon carcinoma cell lines and to accumulate in culture media as a latent enzyme. The cell lines also secrete a physiological inhibitor of cathepsin B, cystatin C. A significant correlation was found between secretion of the latent enzyme and the inhibitor (r = 0.755, P < 0.01). The aim of the present study was to modulate the respective secretion of the two antagonists to test whether or not latency of cathepsin B was due to the concomitant secretion of the inhibitor. SW480 colon carcinoma cells were treated with the acidotropic agent ammonium chloride, phorbol 12-myristate 13-acetate, and the inflammatory cytokines TGF-beta, TNF-alpha, and IL-1 beta. Ammonium chloride significantly increased latent cathepsin B levels without affecting the constitutive secretion of cystatin C. Phorbol 12-myristate 13-acetate induced a 4- to 5-fold increase in secreted latent cathepsin B, but did not alter significantly the accumulation of cystatin C in media. The cytokines, TGF-beta, TNF-alpha, and IL-1 beta, had no major effect on the expression of these two antagonists. Latent cathepsin B released from human carcinoma cells could be efficiently activated by neutrophil elastase at neutral pH. It is concluded that latent cathepsin B is a true proenzyme rather than an enzyme-inhibitor complex. In addition, our data from neutrophil elastase activation experiments indicate that a proteolytic system for activation of the tumor cell-secreted latent enzyme may exist in vivo.
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PMID:Latency of cathepsin B secreted by human colon carcinoma cells is not linked to secretion of cystatin C and is relieved by neutrophil elastase. 820 57


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