Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in mice.
The 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.
Gate
Laurent
L
Fox Chase Cancer Center, Department of Pharmacology, Philadelphia, PA, USA.
Majumdar
Rajrupa S
RS
Lunk
Alexandra
A
Tew
Kenneth D
KD
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000378:metabolism*; D015996:Survival Rate; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D007527:Isoenzymes; D016159:Tumor Suppressor Protein p53; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse