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.