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)

Infection of mice with Leishmania donovani resulted in decreased activities of several liver enzymes involved in the metabolism of xenobiotics. Microsomal membranes from infected livers contained reduced amounts of cytochromes P450 and b5 and NADPH-cytochrome P450 reductase. Several cytochrome P450 isoenzymes (P450-PB1, P450-PB3, P450-PCN and P450-UT1) and P450-mediated reactions (aminopyrine demethylase, aniline hydroxylase, benzphentamine demethylase and ethoxycoumarin deethylase) were affected similarly. The metabolism of two carcinogens (nitrosodimethylamine and 7,12-dimethylbenz[a]anthracene) by liver microsomal membrane preparations was also reduced. Leishmania infection caused an increase of cytosolic epoxide hydrolase and microsomal epoxide hydrolase and NADH-cytochrome b5 reductase were unaffected. The results suggest that Leishmania-infected animals are likely to have altered responses to exogenous toxins compared to uninfected animals.
Mol Biochem Parasitol 1990 Jun
PMID:Changes in hepatic xenobiotic-metabolising enzymes in mouse liver following infection with Leishmania donovani. 211 55

BALB/c 3T3 cells were exposed to 7,12-dimethylbenz[a]anthracene (DMBA) and resultant transformed foci were analyzed for the presence of A182----T mutation at codon 61 of Ha-ras (a mutation found in many DMBA-induced animal tumors). None of the 30 independently cloned transformed cell lines contained such a mutation. In order to see whether DMBA is able to induce this mutation in BALB/c 3T3 cells, we developed a method sensitive enough to detect this specific mutation at the frequency of 10(-6). Employing this assay, we found time- and dose-dependent induction by DMBA of Ha-ras A182----T mutation in BALB/c 3T3 cells; for example, 2 wk after exposure to 100 micrograms/mL DMBA, 1.4 in 1 X 10(4) cells contained this specific mutation. On the other hand, other agents that also induce BALB/c 3T3 cell transformation, such as 3-methylcholanthrene (MCA), 12-O-tetradecanoylphorbol-13-acetate (TPA), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or ultraviolet light, did not induce the mutation at detectable frequency (less than 10(-6)). These results suggest that DMBA efficiently induces Ha-ras mutation in BALB/c 3T3 cells but that this mutation is not recruited in the process of cell transformation. A hypothesis of carcinogen-specific mutation of Ha-ras gene and its tissue (cell type)-specific recruitment in carcinogenesis is proposed.
Mol Carcinog 1990
PMID:Relationship between chemically induced Ha-ras mutation and transformation of BALB/c 3T3 cells: evidence for chemical-specific activation and cell type-specific recruitment of oncogene in transformation. 211 94

Binding affinities of modified steroidal anthrasteroids, 3 beta-hydroxy-3a beta,6-dimethyl-2,3,3a,4,5,8,9,10,10a beta,11,11a beta, 11b alpha-dodecahydro-1H-cyclopenta[a]anthracene-8-one (1) and 3a beta,6-dimethyl-2,3,3a,4,5,8,9,10,10a beta,11,11a beta,11b alpha-dodecahydro-1H-cyclopenta[a]anthracene-3,8-dione (2), the steroid oxendolone and the nonsteroid AA560, for the androgen receptor (AR) of Shionogi carcinoma 115 (SC115) and their effects on the growth of SC115 were investigated in vivo and in vitro. The inhibitory effects of these compounds on testosterone 5 alpha-reductase of SC115 tissues were also measured. The relative binding affinities of these compounds were 3.17-0.03% of that of dihydrotestosterone, and their rank order was (1) greater than AA560 greater than oxendolone much greater than (2). In the presence of 10(-9) M testosterone, anthrasteroids and AA560 inhibited the growth of SC115 cells at 10(-7) M in a serum-free medium, but oxendolone did not. In the absence of testosterone, (1), (2) and oxendolone promoted cell growth at 10(-6), 10(-7) and 10(-7) M, respectively. However, AA560 nearly completely blocked cell growth at 10(-5) M. At a 2 mg daily dose for 13 days, (1) and AA560 powerfully inhibited tumor growth in castrated DS mice treated with testosterone propionate but oxendolone had almost no effect. Anthrasteroids and oxendolone showed weak but significant agonistic activity in vivo. Anthrasteroids markedly inhibited 5 alpha-reductase activity of SC115, oxendolone weakly and AA560 not at all. The remarkable antiandrogenic activities of (1) and AA560 may partially result from their higher affinities for the AR of SC115 but other yet unknown mechanisms may also contribute to these activities.
J Steroid Biochem Mol Biol 1990 Nov 30
PMID:Effects of antiandrogens on growth of androgen-dependent mouse mammary tumor (Shionogi carcinoma 115) in vivo and in vitro. 227 40

Five polycyclic aromatic hydrocarbons (PAHs) of different carcinogenic activities were evaluated for their effects on DNA synthesis (3HTdR labeling index (L.I.] of rat and human mammary epithelial cells (MEC) and for their effects on chromosomes in MEC-mediated sister chromatid exchange (SCE) assays. When compared with DMSO-treated cells, exposures of rat MEC to the two most potent carcinogens (5 micrograms/ml for 24 hr), i.e., 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene (B[a]P), resulted in a 45-62% reduction in the L.I. of rat MEC. Another carcinogen, 20-methylcholanthrene (MCA), produced a 35-48% reduction in L.I., while the noncarcinogenic PAHs, 1,2-benzanthracene (BA) and benzo(e)pyrene (B[e]P), showed no effect. Similarly, exposures of human MEC to DMBA and B[a]P resulted in a 50-90% depression in L.I. while BA was significantly less effective (30% reduction). When co-cultivated with Chinese hamster V-79 cells in the presence of PAH, both rat and human MEC can activate and release the active metabolites to induce SCE in V-79 cells. In the rat MEC-mediated assay for all 5 PAHs, the frequencies of SCE per chromosome in DMBA-, B[a]P-, MCA-, BA-, B[e]P-, and DMSO (solvent control)-treated groups were 6, 3, 1.4, 0.7, 0.4, and 0.3, respectively. DMBA was most effective in increasing SCE, while B[e]P was ineffective. In the human MEC-mediated assay, B[a]P was more effective than DMBA in inducing SCE, and the frequencies of SCE per chromosome were 4.5 and 3.6 in B[a]P- and DMBA-treated groups, respectively. Comparing depression of L.I., SCE, and in vivo carcinogenicity for the 5 PAHs, SCE mediated by rat MEC is better correlated with carcinogenicity in rat than L.I. depression.
Environ Mol Mutagen 1990
PMID:Genotoxic effects of five polycyclic aromatic hydrocarbons in human and rat mammary epithelial cells. 230 52

Expression of four oncogenes and two keratin genes was determined in rat tracheal epithelial cell lines derived from tracheal implants exposed in vivo to 7,12-dimethylbenz[a]anthracene. Cell lines were grouped into four stages of neoplastic progression based on phenotypic markers in order to correlate oncogene expression with stage of malignancy. Northern analysis of RNA revealed a significantly enhanced expression of the c-myc oncogene in the most tumorigenic or tumor-derived cell lines, whereas preneoplastic cells expressed approximately five-fold less transcript. Southern analysis of tracheal cell DNA did not demonstrate amplification of the c-myc gene in any of the positive cell lines. In contrast to c-myc, other oncogenes such as ras and fos were expressed in all cell lines, as well as in control cell cultures, to a similar extent. Patterns of differentiation were examined in these epithelial cell lines by determining the expression of two distinct keratin genes, KA-1 and KB-2. Both malignant and preneoplastic cells expressed the KB-2 gene at variably high levels, whereas the expression of the KA-1 keratin was barely detectable in any of the cell lines. The stage-specific expression of the c-myc oncogene in these tracheal cell lines suggests a correlation between the regulation of certain oncogenes and neoplastic progression in this model of respiratory carcinogenesis.
Mol Carcinog 1989
PMID:Oncogene expression in cell lines derived from rat tracheal implants exposed in vivo to 7,12-dimethylbenz[a]anthracene. 248 55

Primary well-differentiated dimethylbenzene alpha-anthracene (DMBA)-or nitrosomethylurea (NMU)-induced rat mammary adenocarcinomas that are estrogen dependent possess biologically active and immunoreactive transforming growth factor alpha (TGF alpha), which can be detected in a sort agar growth-promoting assay and by a specific liquid-phase competitive RIA, respectively. In contrast, tissue extracts prepared from transplantable undifferentiated DMBA-I and NMU-II rat mammary carcinomas that are estrogen independent and metastatic exhibit low or undetectable levels of TGF alpha. In addition, the primary DMBA- and NMU-induced rat mammary adenocarcinomas express a specific 4.8-kilobase TGF alpha mRNA species, whereas little or no TGF alpha mRNA can be detected in the transplantable DMBA-I and NMU-II tumors. Primary tumors synthesize type IV basement membrane collagen, whereas the transplantable tumors elaborate very little type IV collagen. Either TGF alpha or estrogens can differentially enhance the synthesis of type IV collagen by 0.5- to 4-fold over total protein synthesis in primary cultures of normal mouse mammary epithelial cells or in primary NMU-induced tumor cells, respectively. Therefore, TGF alpha could function as an estrogen-inducible autocrine growth factor for well differentiated rat mammary tumor cells by its ability to selectively regulate type IV collagen synthesis. Estrogens can modulate TGF alpha production in vivo in primary DMBA-induced rat mammary tumors, because ovariectomy results in a rapid decline (within 6 h) of TGF alpha mRNA levels. This response to estrogens can also be observed in vitro. Primary DMBA- or NMU-induced rat mammary tumor cells cultured in the presence of 17 beta-estradiol (10(-8) M) for 4 days show an increase in the level of TGF alpha mRNA over cells not treated with estrogen. This increase in TGF alpha mRNA is paralleled by a 2- to 3-fold increase in the levels of immunoreactive TGF alpha that can be detected and in the conditioned medium from estrogen-treated cells. These results suggest that TGF alpha may be an adjunct marker for those mammary tumors that are well differentiated adenocarcinomas and estrogen dependent and that estrogen-independent tumors do not constitutively produce TGF alpha or express TGF alpha mRNA.
Mol Endocrinol 1987 Oct
PMID:Expression of transforming growth factor alpha (TGF alpha) in differentiated rat mammary tumors: estrogen induction of TGF alpha production. 248 11

We have analyzed the amount of extrachromosomal double-stranded covalently closed circular nonmitochondrial DNA in mouse 3T6 cells by Southern blotting and electron microscopy. Treatment with 7,1-dimethylbenz[a]anthracene, known to promote amplification of integrated SV40 genomes, elevated the amount of circular DNA. Inhibition of DNA synthesis with hydroxyurea, earlier shown to enhance amplification of the cellular dihydrofolate reductase gene, resulted in yet higher levels. Thus, elevation of the frequency of gene amplification and generation of extrachromosomal circular DNA seem to accompany each other in the situations studied in this paper. Two other DNA synthesis inhibitors, aphidicolin and thymidine, had markedly lesser effects on circular DNA. The significance of these findings for the mechanism of gene amplification is discussed.
Somat Cell Mol Genet 1989 Jan
PMID:Increase of extrachromosomal circular DNA in mouse 3T6 cells on perturbation of DNA synthesis: implications for gene amplification. 249 79

Previous studies in this laboratory have demonstrated that exposure of mice to the carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene results in suppression of both humoral and cell-mediated immunity. This suppression is unaccompanied by any significant alteration in splenic lymphocyte subpopulation composition, suggesting that the immune deficit was due to a modulation of lymphocyte function. Additional studies implicated the T helper lymphocyte as the probable target for 7,12-dimethylbenz[a]anthracene-induced immunosuppression, apparently through an inhibition of interleukin 2 production. The purpose of the present study was to examine the mechanism of 7,12-dimethylbenz[a]anthracene-induced T lymphocyte dysfunction at the molecular level and to determine the consequences of 7,12-dimethylbenz[a]anthracene exposure on the interleukin 2 pathway. In vitro exposure of Con A-activated splenocytes to 7,12-dimethylbenz[a]anthracene resulted in suppression of the mitogenic response, suppressed interleukin 2 production, and reduced the expression of the high affinity receptor for interleukin 2. In contrast, expression of the low affinity interleukin 2 receptor was not affected. In addition, interleukin 2-dependent lymphoblasts and long term cultured splenocytes exhibited a dose-dependent decrease in proliferation following in vitro exposure to 7,12-dimethylbenz[a]anthracene. These results suggest that 7,12-dimethylbenz[a]anthracene-induced immunosuppression may be mediated, at least in part, through the interleukin 2/interleukin 2 receptor pathway.
Mol Pharmacol 1989 Jul
PMID:Molecular mechanism of 7,12-dimethylbenz[a]anthracene-induced immunosuppression: evidence for action via the interleukin-2 pathway. 250 53

BALB/MK-2 cells are an epidermal growth factor (EGF)-dependent cell line derived from BALB/c mouse epidermis that can undergo terminal differentiation under appropriate conditions. Previous studies have shown that transformation of these cells by retroviral oncogenes relieves the EGF requirement while blocking the terminal differentiation program. In this report we show that BALB/MK-2 cells are sensitive to transformation by the chemical carcinogens dimethylbenz[a]anthracene (DMBA), 3-methylcholanthrene (MCA), and N-methyl-N'-nitro-N'-nitroso-guanidine (MNNG). BALB/MK-2 cells transformed by these carcinogens proliferate in the absence of EGF and do not undergo terminal differentiation in response to calcium. However, the cells retain their anchorage growth dependence and are nontumorigenic in nude mice. NIH 3T3 transfection analysis showed that the endogenous Ha-ras gene had been activated in both DMBA- and MNNG-transformed cells and the Ki-ras gene had been activated in the MCA-transformed cells. Additionally, non-ras transforming activity was detected in some MNNG-transformed BALB/MK-2 cells. Thus, the BALB/MK-2 cell line provides a reproducible in vitro assay system for chemical transformation of epithelial cells and for identification of oncogene activations associated with changes in growth control and differentiation.
Mol Carcinog 1989
PMID:Activation of ras oncogenes in chemically transformed BALB/MK-2 mouse keratinocytes. 250 87

Three okadaic acid class tumor promoters, okadaic acid, dinophysistoxin-1, and calyculin A, have potent tumor-promoting activity in two-stage carcinogenesis experiments on mouse skin. DNA isolated from tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and each of these tumor promoters revealed the same mutation at the second nucleotide of codon 61 (CAA----CTA) in the c-Ha-ras gene, determined by the polymerase chain reaction procedure and DNA sequencing. Three potent 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, TPA, teleocidin, and aplysiatoxin, showed the same effects. These results provide strong evidence that this mutation in the c-Ha-ras gene is due to a direct effect of DMBA rather than a selective effect of specific tumor promoters.
Mol Carcinog 1989
PMID:Codon 61 mutations in the c-Harvey-ras gene in mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene plus okadaic acid class tumor promoters. 250 60


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