Mutagenesis and carcinogenesis in nucleotide excision repair-deficient XPA knock out mice.
Mice with a defect in the xeroderma pigmentosum group A (XPA) gene have a complete deficiency in nucleotide excision repair (NER). As such, these mice mimic the human XP phenotype in that they have a >1000-fold higher risk of developing UV-induced skin cancer. Besides being UV-sensitive, XPA(-/-) mice also develop internal tumors when they are exposed to chemical carcinogens. To investigate the effect of a total NER deficiency on the induction of gene mutations and tumor development, we crossed XPA(-/-) mice with transgenic lacZ/pUR288 mutation-indicator mice. The mice were treated with various agents and chemicals like UV-B, benzo[a]pyrene and 2-aceto-amino-fluorene. Gene mutation induction in several tumor target- and non-target tissues was determined in both the bacterial lacZ reporter gene and in the endogenous Hprt gene. Furthermore, alterations in the p53- and ras genes were determined in UV-induced skin tumors of XPA(-/-) mice. In this work, we review these results and discuss the applicability and reliability of enhanced gene mutant frequencies as early indicators of tumorigenesis.
van Steeg
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Laboratory of Health Effects Research, National Institute of Public Health and the Environment, RIVM/LEO, pb12 P.O. Box 1, 3720 BA, Eindhoven, Netherlands.
Mullenders
L H
LH
Vijg
J
J
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000633:toxicity; D003043:Cocarcinogenesis; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007763:Lac Operon; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D016296:Mutagenesis; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D001564:Benzo(a)pyrene; D015073:2-Acetylaminofluorene; D007041:Hypoxanthine Phosphoribosyltransferase