p53 heterozygosity results in an increased 2-acetylaminofluorene-induced urinary bladder but not liver tumor response in DNA repair-deficient Xpa mice.
Both nucleotide excision repair (NER) and the p53 tumor suppressor protein play crucial roles in the prevention of cells becoming cancerous. This is clearly demonstrated by the fact that NER-deficient xeroderma pigmentosum patients and Li-Fraumeni patients who carry a germ-line p53 mutation are highly tumor prone. The NER-deficient Xpa and the p53(+/-) mouse models clearly mimic their human counterparts, because they are both tumor prone as well. The aim of the study presented here was to analyze the relative contribution of these two pathways in tumor suppression and to analyze a possible link between NER and p53 activation in vivo. For this, we exposed Xpa, p53(+/-), and Xpa/p53(+/-) mice to 2-acetylaminofluorene (2-AAF). We show that 2-AAF-induced urinary bladder tumor suppression is dependent on p53 status, because p53(+/-) mice were highly tumor prone. Xpa/p53(+/-) mice were even more tumor prone, whereas no increased tumor response was found in Xpa mice. Short-term assays revealed a decreased apoptotic response in Xpa/p53(+/-) mice, pointing in vivo toward a link between NER and p53-mediated apoptosis. In contrast, liver tumor response was primarily dependent on appropriate DNA repair, because Xpa-deficient mice were liver tumor prone. p53 heterozygosity had no influence on liver tumor incidences, in line with the results obtained from the short-term 2-AAF studies revealing no altered cellular response in p53(+/-) or Xpa/p53(+/-) mice. Interestingly, however, mice completely deficient in both NER and p53 (Xpa/p53(-/-) mice) showed a dramatic increase of hepatocellular proliferation accompanied by lacZ reporter gene mutations.
National Institute of Public Health and the Environment, Laboratory of Toxicology, Pathology and Genetics, 3720 BA Bilthoven, the Netherlands.
Esther M
EM
Hoogervorst
Conny Th M
CT
van Oostrom
Rudolf B
RB
Beems
Jan
J
van Benthem
Siska
S
Gielis
Jolanda P
JP
Vermeulen
Piet W
PW
Wester
Joseph G
JG
Vos
Annemieke
A
de Vries
Harry
H
van Steeg
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003433:Crosses, Genetic; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006579:Heterozygote; D007763:Lac Operon / Q000502:physiology; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D014983:Xeroderma Pigmentosum / Q000235:genetics; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D015073:2-Acetylaminofluorene