Abstract
The role of glutathione S‐transferase π (GSTπ) in tumor development has been previously suggested; however the exact function of this enzyme in carcinogenesis remains unclear. GSTπ has been identified as a modulator of cell signaling by interacting with and inhibiting c‐Jun N‐terminal kinase (JNK). This kinase has been in turn described as a regulator of p53 stability and transcriptional activity. To study the possible interaction between GSTπ and p53, we crossed GSTπ‐deficient animals with p53^−/−^ mice. Double knock out animals were viable but developed tumors within 6 months of age; the life span of these animals was however similar to that of GSTπ^+/−^/p53^−/−^ and GSTπ^+/+^/p53^−/−^. Mice heterozygous for p53 lived significantly longer than the p53^−/−^ animals and developed tumors much later, and the expression of GSTπ did not significantly modify the life span of the animals. In contrast, in a wild‐type p53 background, GSTπ^−/−^ mice developed tumors with a significantly higher frequency than heterozygous and wild‐type animals with a median tumor free life span 20 weeks shorter. In addition, in p53^+/+^ background, one third of the GSTπ^−/−^ animals developed lung adenomas, while less than 10% of GSTπ^+/−^ and GSTπ^+/+^ presented such tumors. GSTπ expression did not alter the expression of tumorigenesis markers such as COX‐2 or ornithine decarboxylase in response to phorbol ester. Furthermore, GSTπ‐deficient mouse embryo fibroblasts were more sensitive to H~2~O~2~‐induced apoptosis. P53^−/−^ cells, independent of GSTπ status, were more sensitive to UV and other DNA damaging agents than their wild‐type counterparts. These results suggest that GSTπ may play a protective role in the development of spontaneous tumors.