2.50
Hdl Handle:
http://hdl.handle.net/10541/96955
Title:
Alkyltransferase transgenic mice: probes of chemical carcinogenesis.
Authors:
Gerson, S L; Zaidi, N H; Dumenco, L L; Allay, E; Fan, Chun-Yang; Liu, L; O'Connor, Peter J
Abstract:
Transgenic mice expressing DNA-repair genes are an instructive model with which to study the protective role of DNA-repair pathways in both spontaneous and chemical carcinogenesis. Of particular interest in chemical carcinogenesis is the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which repairs O6-alkylguanine-DNA adducts. Transgenic mice carrying expression constructs for the alkyltransferase gene--either the human MGMT cDNA or the bacterial ada gene--express increased levels of alkyltransferase and have increased capacity to remove O6-methylguanine-DNA adducts. Protection from the DNA damaging effects of N-nitroso compounds occurs specifically in the cells and tissues in which the alkyltransferase transgene is expressed. For instance, mice carrying the PEPCKada construct have increased alkyltransferase in the liver and more rapid removal of O6methylguanine-DNA adducts. The protective effect is noted in hepatocytes, which express PEPCK-linked genes, not in nonparenchymal cells of the liver, which do not. Other tissues that express the transgene in the various models include the thymus, spleen, testes, muscle, stomach and brain. Mice expressing the human alkyltransferase in the thymus have a reduced incidence of thymic lymphomas following exposure to methyl nitrosourea (MNU), evidence of a role for this DNA-repair protein in protection from carcinogenesis due to N-nitroso compounds. Protection has also been observed in the induction of hepatic tumors by N-nitroso-dimethylamine (NDMA). These models will be used to identify whether overexpression of a single DNA-repair gene can block the carcinogenic process of N-nitroso compounds in many different tissues.
Affiliation:
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4937.
Citation:
Alkyltransferase transgenic mice: probes of chemical carcinogenesis. 1994, 307 (2):541-55 Mutat. Res.
Journal:
Mutation Research
Issue Date:
1-Jun-1994
URI:
http://hdl.handle.net/10541/96955
PubMed ID:
7514728
Type:
Article
Language:
en
ISSN:
0027-5107
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorGerson, S Len
dc.contributor.authorZaidi, N Hen
dc.contributor.authorDumenco, L Len
dc.contributor.authorAllay, Een
dc.contributor.authorFan, Chun-Yangen
dc.contributor.authorLiu, Len
dc.contributor.authorO'Connor, Peter Jen
dc.date.accessioned2010-04-21T08:47:14Z-
dc.date.available2010-04-21T08:47:14Z-
dc.date.issued1994-06-01-
dc.identifier.citationAlkyltransferase transgenic mice: probes of chemical carcinogenesis. 1994, 307 (2):541-55 Mutat. Res.en
dc.identifier.issn0027-5107-
dc.identifier.pmid7514728-
dc.identifier.urihttp://hdl.handle.net/10541/96955-
dc.description.abstractTransgenic mice expressing DNA-repair genes are an instructive model with which to study the protective role of DNA-repair pathways in both spontaneous and chemical carcinogenesis. Of particular interest in chemical carcinogenesis is the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which repairs O6-alkylguanine-DNA adducts. Transgenic mice carrying expression constructs for the alkyltransferase gene--either the human MGMT cDNA or the bacterial ada gene--express increased levels of alkyltransferase and have increased capacity to remove O6-methylguanine-DNA adducts. Protection from the DNA damaging effects of N-nitroso compounds occurs specifically in the cells and tissues in which the alkyltransferase transgene is expressed. For instance, mice carrying the PEPCKada construct have increased alkyltransferase in the liver and more rapid removal of O6methylguanine-DNA adducts. The protective effect is noted in hepatocytes, which express PEPCK-linked genes, not in nonparenchymal cells of the liver, which do not. Other tissues that express the transgene in the various models include the thymus, spleen, testes, muscle, stomach and brain. Mice expressing the human alkyltransferase in the thymus have a reduced incidence of thymic lymphomas following exposure to methyl nitrosourea (MNU), evidence of a role for this DNA-repair protein in protection from carcinogenesis due to N-nitroso compounds. Protection has also been observed in the induction of hepatic tumors by N-nitroso-dimethylamine (NDMA). These models will be used to identify whether overexpression of a single DNA-repair gene can block the carcinogenic process of N-nitroso compounds in many different tissues.en
dc.language.isoenen
dc.subjectLiver Canceren
dc.subjectThymus Canceren
dc.subject.meshActins-
dc.subject.meshAlkylating Agents-
dc.subject.meshAnimals-
dc.subject.meshAnticarcinogenic Agents-
dc.subject.meshCarcinogens-
dc.subject.meshDNA Repair-
dc.subject.meshFemale-
dc.subject.meshGene Expression Regulation, Enzymologic-
dc.subject.meshImmunoenzyme Techniques-
dc.subject.meshLiver Neoplasms, Experimental-
dc.subject.meshLymphoma-
dc.subject.meshMale-
dc.subject.meshMethylnitrosourea-
dc.subject.meshMethyltransferases-
dc.subject.meshMice-
dc.subject.meshMice, Transgenic-
dc.subject.meshModels, Genetic-
dc.subject.meshNitroso Compounds-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshPhosphoenolpyruvate Carboxykinase (GTP)-
dc.subject.meshPromoter Regions, Genetic-
dc.subject.meshThymus Neoplasms-
dc.titleAlkyltransferase transgenic mice: probes of chemical carcinogenesis.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4937.en
dc.identifier.journalMutation Researchen
All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.