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Gate L , Majumdar RS , Lunk A , Tew KD
Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in mice
International Journal of Cancer. 2005 Jan 1;113(1) :29-35
AbstractThe role of glutathione S-transferase pi (GSTpi) in tumor development has been previously suggested; however the exact function of this enzyme in carcinogenesis remains unclear. GSTpi 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 GSTpi and p53, we crossed GSTpi-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 GSTpi(+/-)/p53(-/-) and GSTpi(+/+)/p53(-/-). Mice heterozygous for p53 lived significantly longer than the p53(-/-) animals and developed tumors much later, and the expression of GSTpi did not significantly modify the life span of the animals. In contrast, in a wild-type p53 background, GSTpi(-/-) 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 GSTpi(-/-) animals developed lung adenomas, while less than 10% of GSTpi(+/-) and GSTpi(+/+) presented such tumors. GSTpi expression did not alter the expression of tumorigenesis markers such as COX-2 or ornithine decarboxylase in response to phorbol ester. Furthermore, GSTpi-deficient mouse embryo fibroblasts were more sensitive to H(2)O(2)-induced apoptosis. P53(-/-) cells, independent of GSTpi status, were more sensitive to UV and other DNA damaging agents than their wild-type counterparts. These results suggest that GSTpi may play a protective role in the development of spontaneous tumors.
NotesUnited States Journal Article