Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported that transin RNA, a 1.9-kb RNA coding for a novel, secreted proteinase, was overexpressed during the progression of benign mouse skin papillomas to malignant squamous cell carcinomas (SCCs) induced by a two-stage protocol (Proc Natl Acad Sci USA 83:9413, 1986). Recently a high degree of similarity has been demonstrated between rabbit stromelysin, a secreted metalloproteinase that degrades proteoglycans found in the basement membrane and the amino acid sequence predicted in rat transin cDNA. DNA sequencing of a mouse cDNA isolated from an SCC (initiated by 7,12-dimethylbenz[a]anthracene [DMBA] and promoted by 12-O-tetradecanoylphorbol-13-acetate [TPA]) showed greater than 85% nucleotide similarity and 90% amino acid similarity to the rat transin-1 cDNA nucleotide and predicted amino acid sequences. Using this mouse transin cDNA clone as a probe (labeled with 32P) we found enhanced levels of transin mRNA transcripts in SCCs induced by a protocol giving rise to metastatic tumors (repeated N-methyl-N-nitroso-N'-nitroguanidine [MNNG] treatments) compared with the level found in SCCs induced by a protocol that had a lower probability of giving rise to metastatic tumors (MNNG initiation followed by TPA promotion). A study of primary SCCs and metastatic lesions induced by repeated benzo[a]pyrene treatment showed that the levels of transin mRNA transcripts were reduced in the metastatic lesions in comparison to the primary tumors. Southern analysis of the DNA isolated from epidermis, papillomas, and SCCs indicated that neither transin gene amplification nor rearrangement accounted for increased levels of the transin mRNA transcripts. These data suggest a role for enhanced levels of transin production in the invasion and metastasis of chemically induced SCCs.
Mol Carcinog 1988
PMID:Expression pattern of a gene for a secreted metalloproteinase during late stages of tumor progression. 315 Dec 58

Two outbred lines of CD-1 mice were developed using males and females in an initiation (dimethylbenz[a]anthracene; DMBA), promotion (12-O-tetradecanoylphorbol-13-acetate; TPA) challenge, posttumorigenesis breeding protocol. Our results indicate that the phorbol ester-sensitive (PESTI) line developed tumors at a rate 4.1 times faster than the CD-1 parental line, while the phorbol ester-resistant (PERTI) line developed tumors at a rate 36 times slower than the CD-1 parents. The average number of tumors per mouse reached levels of 27.5 at 12 wk in the PESTI line, 0.1 at 16 wk in the PERTI line, and 6.7 at 16 wk in the CD-1 line. Biochemical tests showed that the PESTI line had both a high basal level and an enhanced epidermal ornithine decarboxylase (E.C. 4.1.1.17) response to TPA, the latter being nine times that of the PERTI line at their maximum dosages. An autoradiographic analysis of in vivo epidermal cell protein phosphorylation indicated marked differences in basal protein phosphorylation profiles (with high phosphate incorporation, PERTI, 112.7, 95.5, 64.4, 40.8, 18.6, 17.4, and 12.3 kDa; PESTI, 64.4, 40.8, 31.8, and 12.3 kDa) as well as TPA-dependent changes in these profiles (difference from basal levels, PERTI, 31.8 and 12.8 kDa; PESTI, 139.6, 126.3, 37.2, and 18.6 kDa). These heterogeneous profiles indicate strong genetic segregation of these protein kinase C target substrates.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Carcinog 1988
PMID:Tumorigenic and molecular characterization of novel phorbol ester-resistant and -sensitive lines of mice. 315 Dec 59

DNA from five lines of transformed bladder epithelial cells derived from cultures of primary cells that had been treated with 7,12-dimethylbenz[a]anthracene (DMBA) can transform NIH 3T3 mouse fibroblasts in DNA transfection experiments. Southern analysis of DNA from NIH 3T3 primary and secondary transformants established that four of the DMBA-transformed cell lines contained activated cellular Ki-ras, while the remaining cell line contained a transforming gene that is unrelated to Ki-ras, N-ras, and Ha-ras. The point mutations responsible for Ki-ras activation were detected using oligonucleotide probes following selective amplification of Ki-ras specific sequences using the polymerase chain reaction. The results showed that activation of Ki-ras invariably involved a GC----AT transition mutation of the first position of codon 12. Surprisingly, a Ki-ras gene that was activated by a GC----AT transition mutation at the same position was also detected in a single transformed bladder urothelial cell line derived from control cultures of mouse bladder cells. Together, our results indicate that Ki-ras activation in the DMBA-transformed bladder cell lines may not be a direct consequence of interaction of activated DMBA metabolites with the Ki-ras gene.
Mol Carcinog 1988
PMID:Activated Ki-ras genes in bladder epithelial cell lines transformed by treatment of primary mouse bladder explant cultures with 7,12-dimethylbenz[a]anthracene. 315 Dec 61

Enzymatic activation of polycyclic aromatic hydrocarbons (PAHs) and its effect on cytotoxicity were studied using the neutral red viability assay as the end point. Benzo[a]pyrene was progressively cytotoxic to human hepatoma (HepG2) cells over a 1- to 3-d period, and after induction of monooxygenase activity with a polychlorobiphenyl (PCB) mixture (Arochlor 1254), cytotoxicity was increased about threefold. Concomitant with Arochlor exposure was an increase in the activity of 7-ethoxycoumarin odeethylase, which could be inhibited by exposure to alpha-naphthoflavone. Human keratinocytes (NHEK), but not fibroblasts (HFF), were sensitive to the cytotoxicity of benzo[a]pyrene. However, preexposure of the keratinocytes to Arochlor did not increase their sensitivity to benzo[a]pyrene. Neither the keratinocytes, fibroblasts, nor HepG2 cells were sensitive to acenaphthene. Addition of hamster or rat hepatic S9 mix, however, resulted in toxicity from benzo[a]pyrene and acenaphthene. 7,12-Dimethylbenz[a]anthracene was only mildly cytotoxic to the fibroblasts, and its cytotoxicity was not enhanced in the presence of rat or hamster S9 mix. Exposure of the HepG2 cells to 7,12-dimethylbenz[a]anthracene showed progressive toxicity over a 1- to 3-d period. Prior exposure of the HepG2 cells to Arochlor did not enhance their sensitivity to 7,12-dimethylbenz[a]anthracene. Human keratinocytes were sensitive to 7,12-dimethylbenz[a]anthracene, with cytotoxicity markedly increasing over a 1- to 3-d period.
Mol Toxicol
PMID:Mediating role of metabolic activation in in vitro cytotoxicity assays. 315 1

Three genotoxic carcinogens and eight tumor promoters were tested for induction of aneuploidy, specifically chromosome loss, in Saccharomyces cerevisiae D61.M. This is a heterozygous diploid yeast strain that permits the scoring of segregants expressing three linked recessive markers (cyhR2, ade6, and leu1), two of which (ade6 and leu1) are located close to the centromere on opposite arms of chromosome VII. The centromere marker leu was routinely checked, and a positive control (bavistan) was run with every experiment. The three genotoxic carcinogens aflatoxin B1, benzo(a)pyrene, and 7,12-dimethylbenz(a)anthracene did not induce aneuploidy, independent of the presence or absence of an exogenous metabolic activation system (rat liver homogenate; S9). Four of the eight tumor promoters tested induced chromosome loss but not mitotic recombination or mutation: cholic acid, lithocholic acid, phenobarbital, and saccharin. Diethylstilbestrol (DES) led to positive as well as to negative results in several independent experiments. In the case of the positive experiment, DES also induced putative recombinants. Three tumor promoters induced neither chromosome loss nor mitotic recombination: anthralin, 4,4'-dichloro-diphenyl-ethane (DDT) and gamma-hexachlorcyclohexane (lindane). From our experiments it can be concluded that the hypothesis put forward by Parry et al. [Nature; 294:263-265], according to which tumor promoters induce chromosome loss in yeast, is not correct in a general sense. In our set of eight tumor promoters, only one half distinctly induced chromosome loss.
Environ Mol Mutagen 1988
PMID:Induction of mitotic chromosome loss in the diploid yeast Saccharomyces cerevisiae D61.M by genotoxic carcinogens and tumor promoters. 328 49

Incubation of the carcinogenic polycyclic aromatic hydrocarbon dibenz[a,h]anthracene (DBA) with liver microsomes of Sprague-Dawley rats, pretreated with Aroclor 1254, yielded more than 30 metabolites. Fifteen of these could be identified, and they account for 95% of the ethyl acetate-extractable metabolites of DBA. Twelve metabolites were identified for the first time, by chromatographic and spectroscopic methods: these were DBA-5,6-oxide, 1-, 2-, 3-, 4-, 5-, 6-phenols, 3,4:12,13-bis-dihydrodiol, 1,4/2,3-tetrol, 1,3/2,4-tetrol, 3,4-catechol, and a phenol dihydrodiol derived from the 2-phenol. Quantitative determination revealed that the attack of cytochrome P-450 dependent monooxygenases occurs at the 1,2-, 3,4- and 5,6-positions of the DBA molecule in the ratio 1.7:1.9:1.0. Evidence is presented which indicates that the phenols of DBA are formed by aromatization of the initially generated arene oxides, rather than by direct hydroxylation. The index Ni obtained by refined perturbational molecular orbital calculations was found to be superior to the reactivity number Nt in predicting the predominant phenols, i.e., 2-, 4-, and 5-phenols, formed by aromatization of the corresponding arene oxides. Their enzymatic hydrolysis leads to the formation of trans-dihydrodiols, of which the 3,4-isomer dominates the microsomal metabolites of DBA accounting for more than 22% of the total metabolic conversion, compared to the 1,2-dihydrodiol with 11-16% and the 5,6-dihydrodiol with 2%. These metabolites were obtained as enantiomeric-enriched mixtures in which the R,R enantiomer of the 1,2-dihydrodiol prevailed with 84%, of the 3,4-dihydrodiol with 79% and of the 5,6-dihydrodiol with 96%. The metabolic pathway via the 1,2-dihydrodiol proceeds to the vicinal diol epoxides, as indicated by the products of hydrolysis the 1,4/2,3- and 1,3/2,4-tetrols. No evidence for the formation of vicinal dihydrodiol epoxides from the 3,4-dihydrodiol, one of the most mutagenic and carcinogenic metabolite of DBA, could be found. In this case, tetrol epoxides have been proposed as ultimate reactive metabolites. Tetrol epoxides can also be formed from DBA-5,6-dihydrodiol via the identified 3,4:12,13-bis-dihydrodiol. This unprecedented metabolic behavior of a carcinogenic polycyclic aromatic hydrocarbon could have its cause in the high molecular symmetry of DBA which permits subsequent metabolic attacks at discrete, but structurally equivalent sites of the molecule.
Mol Pharmacol 1987 Nov
PMID:Regio- and stereoselective metabolism of dibenz[a,h]anthracene: identification of 12 new microsomal metabolites. 368 68

Cytochrome P-450-dependent aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase activities of a cloned line of human lymphoblastoid AHH-1 cells are inhibited by a monoclonal antibody (MAb 1-7-1) prepared to a 3-methylcholanthrene-induced rat liver cytochrome P-450. The monoclonal antibody inhibition determined that a single MAb 1-7-1-sensitive type of cytochrome P-450 is responsible for all of AHH expression in both the basal and benz[a]anthracene-induced cells. Partial inhibition by the MAb 1-7-1, however, indicates that at least two forms of cytochrome P-450 catalyze 7-ethoxycoumarin O-deethylase in both the basal and the induced cells, one form of which is identical to the MAb-sensitive cytochrome P-450 responsible for all of the AHH. Thus, a single cloned cell line is capable of expressing two classes of cytochromes P-450, and the observed multiplicity of cytochrome P-450 in animal tissues does not necessarily depend on cell heterogeneity. A sensitive MAb 1-7-1-based radioimmunoassay also directly demonstrates the presence in these cells of a MAb 1-7-1-specific type of cytochrome P-450 as well as its elevation in the induced cells. These MAb-based methods thus can determine the contribution of specific MAb-defined types of cytochromes P-450 to the cellular metabolism of specific xenobiotics.
Mol Pharmacol 1985 Jun
PMID:Monoclonal antibody-directed determination of cytochrome P-450 types expressed in a human lymphoblastoid cell line. 387 98

Metabolism of 7-chlorobenz(a)anthracene (7-Cl-BA) by liver microsomes from untreated rats, and from rats pretreated with either 3-methylcholanthrene or phenobarbital was studied. The metabolites were isolated by HPLC and characterized by UV-visible, mass, and proton NMR spectral analyses and identified as 7-Cl-BA trans-3,4-, 5,6-, and 8,9-dihydrodiols, 3-hydroxy-7-Cl-BA, and 4-hydroxy-7-Cl-BA. Proton NMR spectral analysis indicated that 7-Cl-BA trans-3,4-dihydrodiol preferentially adopted a quasidiequatorial conformation while trans-5,6- and 8,9-dihydrodiols preferentially adopted a quasidiaxial conformation. Comparison of circular dichroism spectra with those of 7-bromobenz(a)anthracene trans-dihydrodiol metabolites of known absolute stereochemistry indicated that the major enantiomeric 7-Cl-BA trans-3,4-, 5,6-, and 8,9-dihydrodiols had R,R absolute configuration. Application of chiral stationary phase HPLC for direct resolution of the trans-dihydrodiols and their hydrogenated and dechlorinated derivatives enabled determination of the optical purity of each dihydrodiol metabolite obtained from the three microsomal systems. In vitro incubation of 7-Cl-BA under molecular oxygen-18 produced 7-Cl-BA trans-3,4-, 5,6-, and 8,9-dihydrodiols, each containing one oxygen-18 atom. Mass spectral analysis of the dehydration products of the oxygen-18-containing trans-dihydrodiol metabolites indicated that 7-Cl-BA 3S,4R-epoxide and 7-Cl-BA 8R,9S-epoxide were the predominant enantiomeric intermediates.
Mol Pharmacol 1985 Jul
PMID:Stereoselective metabolism of 7-chlorobenz(a)anthracene by rat liver microsomes. Absolute configurations and optical purities of trans-dihydrodiol metabolites. 402 98

The surface morphology of normal mammary glands and mammary carcinomas was examined under the scanning electron microscope after digestion of connective tissue and the basal lamina with collagenase, hyaluronidase and hydrochloric acid (HCl). Two types of cells were clearly identified in the acini of normal glands; granular epithelial cells and stellate myoepithelial cells. Spindle-shaped myoepithelial cells lying longitudinally along the mammary ducts were also recognized. 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas consisted of irregular masses of cells which had polypoid or columnar processes with rounded heads; the masses appeared to be composed of a single type of rhomboid cell. The tumors lacked the stellate or spindle-shaped myoepithelial cells found in normal acini and ducts.
Virchows Arch B Cell Pathol Incl Mol Pathol 1980
PMID:Scanning electron microscopy of 7,12-dimethylbenz(a)-anthracene-induced mammary carcinoma in the female Sprague-Dawley rat. 610 17

The long-term (34 weeks) topical administration of 7,12-dimethylbenz(a)anthracene (DMBA) to the skin of male and female Mastomys induced a broad spectrum of benign and malignant tumors in all animals treated. In a two-stage carcinogenesis experiment with topical initiation with DMBA and topical promotion with TPA, 50% of the animals developed both benign and malignant skin tumors. In general, benign tumors occurred between weeks 15 and 25, whereas malignant tumors were seen 40 weeks after initiation. In contrast to the situation in Mus musculus, the benign tumors consisted mainly of keratoacanthomas instead of fibroepitheliomas. In the non-initiated, TPA-treated, control group four benign and four malignant tumors were seen, whereas animals of the DMBA-initiated, acetone-treated control group were free of tumors. The promotion of virus transformed cells with TPA is discussed.
Virchows Arch B Cell Pathol Incl Mol Pathol 1981
PMID:Chemical carcinogenesis by the two-stage protocol in the skin Mastomys natalensis (Muridae) using topical initiation with 7,12-dimethylbenz(a)anthracene and topical promotion with 12-0-tetradecanoylphorbol-13-acetate. 611 33


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