Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in mice

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+/+/n53-/-. 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 H2O2-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. © 2004 Wiley-Liss, Inc.