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)

In this study we analyzed the mutations in c-Ha-ras from skin papillomas initiated with benzo[a]pyrene (B[a]P), 7-methylbenz[a]anthracene (7-MBA), and 10-fluoro-7-methylbenz[a]anthracene (10-F-7-MBA) and from papillomas induced by treatment with tumor promoter alone. Among the papillomas induced by treatment with tumor promoter alone, 56% (nine of 16) had mutations in c-Ha-ras. These mutations were found primarily in codon 61 and included both A182-->T and A182-->G mutations. In addition, one promoter-induced tumor had a G35-->A mutation in codon 12, and one had a G37-->C mutation in codon 13. The other promoter-induced papillomas did not have detectable mutations in codons 12, 13, or 61. Most of the B[a]P-initiated papillomas (77%; 10 of 13) did not have detectable mutations in c-Ha-ras codons 12, 13, or 61. However, three of these B[a]P-initiated papillomas had c-Ha-ras codon 13 mutations; one had a G37-->C transversion and two had G38-->T transversions. Most of the 7-MBA-initiated tumors and all of the 10-F-7-MBA-initiated tumors had an activated c-Ha-ras gene [nine of 10 (90%) and 11 of 11 (100%), respectively]. These mutations were almost exclusively A182-->T transversions in codon 61 except for two 7-MBA-initiated papillomas that had G37-->C transversions in codon 13. The results suggest that more than one mechanism may contribute to activation of c-Ha-ras by polycyclic aromatic hydrocarbons (PAHs) in mouse skin. Furthermore, the absence of c-Ha-ras mutations in most B[a]P-initiated papillomas, as well as in a significant fraction of those induced by tumor promoter alone, suggests that there may be other molecular targets involved in tumor initiation by PAHs in mouse skin.
Mol Carcinog 1993
PMID:Further analysis of c-Ha-ras mutations in papillomas initiated by several polycyclic aromatic hydrocarbons and papillomas from uninitiated, promoter-treated skin in SENCAR mice. 828 Mar 75

The expression pattern of transforming growth factor-beta 1 (TGF-beta 1) during the stages of complete carcinogenesis in the hamster cheek pouch model was studied. The right cheek pouches of 18 male hamsters were treated with 0.5%, 7,12-dimethylbenz[a]anthracene (DMBA) for 16 wk. TGF-beta 1 was detected immunohistochemically in the resulting samples with two different polyclonal monospecific antibodies that recognize intracellular and extracellular forms of TGF-beta 1. In the normal cheek pouch, extracellular protein stained the corium strongly, but the reaction was not evenly distributed. As treatment progressed, the reaction increased in both area and intensity; the peak was reached at 8 wk. Intracellular TGF-beta 1 expression followed a similar pattern, with a peak at 4 wk of treatment. The results of northern blot analysis were concordant with the immunohistochemical results. Overexpression of TGF-beta 1 was also observed in the malignant tumors, but only the extracellular form of the protein was present; intracellular TGF-beta 1 was not detected in these tumors. The expression of TGF-beta 1 in this carcinogenesis model seems to have two formal stages, the first being an overexpression step as a reaction to the uncontrolled growth and the second being one in which tumors have no internal expression of TGF-beta 1 but in which external protein accumulates in the surrounding stroma. A possible explanation of this paradox may be that TGF-beta 1 has functions other than its growth-repressing activity.
Mol Carcinog 1994 Jan
PMID:Transforming growth factor-beta 1 expression in Syrian hamster cheek pouch carcinogenesis. 829 79

There is significant evidence that the ras oncogene plays a role in experimental mammary carcinogenesis; the evidence in human breast cancer, however, is more limited. We induced the expression of transformation phenotypes in the human breast epithelial cell line MCF-10F with the chemical carcinogens 7,12-dimethylbenz[a]anthracene, N-methyl-N-nitrosourea, N-methyl-N-nitro-N'-nitrosoguanidine, and benzo[a]pyrene. This work was designed to clarify whether chemically induced neoplastic transformation correlates with alterations in the ras gene. MCF-10F cells have two c-Ha-ras alleles, identified by 1.0-kb and 1.2-kb restriction fragments. Treatment with carcinogens resulted in the loss of one of the alleles (1.0 kb). Polymerase chain reaction-amplified DNA from all carcinogen-treated cells was analyzed for point mutations in c-Ha-ras at codons 12 and 61. All of the carcinogens induced a mutation of the remaining allele at the first position of codon 12 (GGC-->AGC). Another frequent mutation occurred at the first position of codon 61 (CAG-->GAG). The changes in c-Ha-ras were associated with the emergence of colony formation in agar-methocel, but no specific changes in this gene correlated with the emergence of invasiveness or tumorigenesis, indicating that other genes may be involved in the process.
Mol Carcinog 1994 Jan
PMID:Allele loss and point mutation in codons 12 and 61 of the c-Ha-ras oncogene in carcinogen-transformed human breast epithelial cells. 829 85

Treatment of the dorsal epidermis of SENCAR mice with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced a time- and dose-dependent stimulation of interleukin-1 alpha (IL-1 alpha) gene expression. Levels of IL-1 alpha mRNA were elevated as early as 15 min and peaked at 3-4 h after a single application of TPA (2 micrograms or 10 micrograms). IL-1 alpha gene expression increased in epidermal tissue isolated from SENCAR mice at 1, 3, 6, 10, 16, and 22 wk after a single treatment with 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA) and subsequent twice-weekly application of 2 micrograms TPA. IL-1 alpha-immunoreactive protein was specifically localized within suprabasal keratinocytes in cutaneous tissue isolated from mice treated with DMBA-TPA for 1-22 wk and in nonproliferating cells located within papilloma tissue isolated from SENCAR mice at 22 wk after initiation and promotion. Basal cells within hyperplastic epidermis did not produce IL-1 alpha-immunoreactive protein. DMBA treatment alone did not induce IL-1 alpha gene expression. Injection of IL-1 alpha-specific antibodies (50 micrograms) into SENCAR mice via the tail vein 2 h before treatment with TPA (2 micrograms or 10 micrograms) significantly (P < 0.05) inhibited the skin thickening usually observed 24 h after treatment with TPA. Autoradiography studies showed that injection of anti-IL-1 alpha antibodies inhibited incorporation of [methyl-3H]thymidine by keratinocytes within the epidermis and by cells within hair follicles. It also inhibited neutrophil infiltration into the dermis, which usually results from topical application of TPA. These data suggest that IL-1 alpha is a pivotal cytokine produced by specific subpopulations of epidermal keratinocytes and that IL-1 alpha primarily regulates the epidermal proliferative response of a distinctly separate population of keratinocytes after topical exposure of murine epidermis to TPA and secondarily modulates neutrophil migration into the dermis. Consequently, manipulation of IL-1 alpha may be a way to attenuate or abrogate the cutaneous response to TPA by altering keratinocyte proliferation, the resultant hyperplasia, and a portion of the inflammatory response characterized by dermal infiltration of neutrophils.
Mol Carcinog 1993
PMID:Interleukin-1 alpha gene expression and localization of interleukin-1 alpha protein during tumor promotion. 835 83

In the present study we have investigated the capacity of various compounds sterically related to indolo[3,2-b]carbazole to inhibit specific 2,3,7,8-tetrachloro[1,6-3H]dibenzo-p-dioxin binding in rat liver cytosol, as analyzed by electrofocusing in polyacrylamide gels. When the two nitrogen atoms of indolo[3,2-b]carbazole (IC50 = 3.6 nM) were replaced with sulfur atoms, the affinity for the specific binding sites (IC50 = 3.3 nM) was similar to that of the parent compound, whereas the affinity decreased when the two nitrogen atoms were replaced with oxygen atoms (IC50 = 29 nM). Substitution with methyl groups at positions 5 and 11 (on the nitrogens) of indolo[3,2-b]carbazole resulted in increased affinity (IC50 = 1.2 nM), compared with that of the parent compound, whereas dimethylation at the 4,10- or 2,8-positions decreased the affinity (IC50 = 19 nM and IC50 > 150 nM, respectively). Substitution at positions 5 and 11 of indolo[3,2-b]carbazole with substituents larger than methyl, as in 5,11-diethylindolo[3,2-b]carbazole (IC50 = 8.9 nM), diacetylindolo[3,2-b]carbazole (IC50 = 11.2 nM), 5,11-dibutylindolo[3,2-b]carbazole (IC50 > 150 nM), and 5,11-di(N,N-dimethylaminoethyl)indolo[3,2-b]carbazole (IC50 > 1500 nM), also decreased the affinity. Introduction of oxygen in, or hydroxylation of, the middle ring of indolo[3,2-b]carbazole, giving indolo[3,2-b]carbazole-6,12-quinone (IC50 > 150 nM) or 6,12-dihydroxyindolo[3,2-b]carbazole (IC50 > 1500 nM), respectively, also lowered the affinity. We calculated the Gibbs free energy of solvation of the analogue isoquino[3,4-b]phenanthridine (IC50 = 137 nM), relative to that of dibenz[a,h]anthracene (IC50 = 2.5 nM), in water to be -6 kcal/mol by free energy perturbation, which indicates that the most important explanation for the observed difference in binding affinity is the smaller difference in relative free energy of binding at the binding sites, compared with the Gibbs free energy of solvation of the two compounds.
Mol Pharmacol 1993 Aug
PMID:Interactions of indolo[3,2-b]carbazoles and related polycyclic aromatic hydrocarbons with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver. 839 90

7,12-Dimethylbenz[a]anthracene (DMBA) produced a dose-related suppression of in vitro polyclonal antibody response to lipopolysaccharide in mouse splenocytes co-cultured with rat hepatocytes. Addition of alpha-naphthoflavone (ANF), the cytochrome P-450 inhibitor, to the coculture reversed the DMBA-induced immunosuppression. The amount of [3H]DMBA bound to splenocyte DNA increased in a time-dependent manner up to 4 hr of co-culture and treatment of ANF reduced the binding. The addition of extracellular DNA to the co-culture prevented the suppression of the antibody response by DMBA. These results suggested that reactive metabolite(s) of DMBA were released from hepatocytes and that the suppression of the antibody response by DMBA is mediated via these reactive intermediate(s). DNA represents the primary macromolecular target for the reactive intermediate(s) of DMBA.
Biochem Mol Biol Int 1993 Feb
PMID:Suppression of the in vitro immune response by 7,12-dimethylbenz[a]anthracene in mouse splenocytes co-cultured with rat hepatocytes. 849 21

Acetaminophen was demonstrated to maintain cytochrome P450 1A1 (P450 1A1) in isolated rainbow trout liver cells cultured in serum-free medium. This novel finding was characterized in detail. Cultured trout liver cells retained their ability to respond to typical 1A1 inducers in vitro; induction of ethoxyresorufin O-deethylase (EROD) activity was readily demonstrated by exposing liver cells from control trout to beta-naphthoflavone (BNF), Aroclor 1254, or 7,12-dimethylbenz[a]anthracene. BNF was the most potent inducer studied and was used in further experiments. High levels of EROD activity, immunoreactive 1A1, and 1A1 mRNA were expressed in liver cells prepared from trout pretreated with BNF. However, all of these 1A1-specific indicators rapidly declined when cells from BNF-treated trout were placed in culture, and BNF in culture medium was not effective in maintaining EROD activity. Immunohistochemical studies suggested that addition of acetaminophen to liver cells prepared from BNF-induced trout helped maintain elevated levels of P450 1A1. Total cytochrome P450, EROD activity and immunoreactive P450 1A1 were retained in liver cells from BNF-induced trout by the addition of acetaminophen, in a dose-dependent manner. The concentrations of acetaminophen most effective in maintaining P450 1A1 produced cytotoxic effects, including vesiculation of endoplasmic reticulum. Furthermore, the acetaminophen maintenance of P450 1A1 was primarily attributed to elevated levels of P450 1A1 mRNA. In contrast to BNF, acetaminophen was not capable of inducing 1A1 in liver cells prepared from control trout. This is the first report to demonstrate that acetaminophen can help maintain P450 1A1 and that this effect is exerted at the level of P450 1A1 mRNA.
Exp Mol Pathol 1993 Apr
PMID:Acetaminophen toxicity in cultured trout liver cells. II. Maintenance of cytochrome P450 1A1. 849 16

Microsatellite instability (MI) and loss of heterozygosity (LOH) were examined in mammary tumors induced in Sprague-Dawley x F344 F1 female rats by 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Examination of 62 microsatellite loci revealed MI in nine of 15 (60%) PhIP-induced mammary tumors, and five of these MI-positive tumors had mutations in more than one microsatellite locus. In contrast, two of 12 (17%) 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were MI positive but had mutations at only one locus each. Further, by using 37 polymorphic markers specific LOH was observed in four of 15 PhIP induced mammary tumors on distal parts of rat chromosome 10, which is homologous to human chromosome 17q with no background level of LOH. Similarly, DMBA-induced mammary tumors showed specific LOH on the same region of chromosome 10. These data suggest that mismatch-repair deficiency and loss of chromosome 10 are involved in carcinogenesis of PhIP-induced rat mammary tumors.
Mol Carcinog 1996 Mar
PMID:Microsatellite instability and loss of heterozygosity on chromosome 10 in rat mammary tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 859 30

The somatic mutation and recombination test (SMART) in Drosophila melanogaster allows screening of chemicals for genotoxicity in a multicellular organism. In order to correlate data obtained in the SMART with those from genotoxicity tests in rodents, it is important to learn more on the variety of drug-metabolizing enzymes present in this insect and to identify their substrate specificities. In this study we have concentrated on the phase I enzyme cytochrome P450 6A2, which is the first cytochrome P450 cloned from Drosophila. A genomic CYP6A2 DNA fragment and its corresponding cDNA were cloned and sequenced, revealing a previously unidentified intron with an inframe stop codon. This intron is invariantly present in an insecticide resistant [OR(R)] and a sensitive (flr3) strain. Developmental Northern analysis of CYP6A2 mRNA demonstrated a peak of expression in the third larval and pupal stage. CYP6A2 mRNA was found to be present in the insecticide-resistant strain at higher levels than in the insecticide-sensitive strain. Therefore, insecticide resistance might be correlated with enhanced CYP6A2 expression. The substrate specificity of CYP6A2 enzyme was investigated by coexpressing CYP6A2 cDNA with the cDNA for human NADPH-cytochrome P450 reductase in the yeast Saccharomyces cerevisiae. The transformed strain activated the mycotoxin aflatoxin B1 to a product that induced gene conversion, scored at the trp5 locus. Two other compounds, 7,12-dimethylbenz[a]anthracene (DMBA) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), were metabolized in the transformed strain to cytotoxic products.
Environ Mol Mutagen 1996
PMID:Metabolism of promutagens catalyzed by Drosophila melanogaster CYP6A2 enzyme in Saccharomyces cerevisiae. 862 48

We established a new squamous cell carcinoma cell line, designated RSS18, from a 7,12-dimethyl-benz[a]anthracene (DMBA)-induced submandibular gland of the female rat, and investigated a testosterone metabolism in the cells. During 6 h incubation of RSS18 cells with testosterone as a substrate, the cells produced a significant amount of 5alpha-dihydrotestosterone (DHT) and three kinds of minor metabolites, and their percentages metabolized against total metabolites were in descending order of DHT (89 %) > 5alpha-androstane-3alpha,17beta-diol (9.0 %) > 5alpha-androstanedione(1.6%) > 4-androstene-3,17-dione (0.69%). Therefore, testosterone in RSS18 cells was predominantly converted to DHT by 5alpha-reductase. Growth of RSS18 cells was stimulated by DHT (10(-11)-10(-9) M) to around 170%. By reverse transcription-polymerase chain reaction, the androgen receptor mRNA was significantly detected in RSS18 cells. As a result of these findings, DHT production from testosterone and expression of androgen receptor mRNA, we concluded that RSS18 proliferation may be stimulated by DHT through 5alpha-reductase from testosterone.
J Steroid Biochem Mol Biol 1996 Mar
PMID:Testosterone metabolism in new squamous cell carcinoma cell line (RSS18) from 7,12-dimethylbenz[a]anthracene-induced submandibular gland of female rat. 863 71


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