Tissue-specific activation of tumor marker glutathione transferase P transgenes in transgenic rats.

By means of transgenic rats, we have recently shown that the GPEI enhancer of the glutathione transferase P (GST-P) gene, which has two one-base-missmatched AP-1 sites locating palindromically with three-base spacing in between, is sufficient for conferring tumor-specific activation of the gene in vivo. It is noted that there is another consensus AP-1 site near the promoter of this gene. By using seven independent transgenic rats, bearing distinct areas of the GST-P gene that are connected to the chloramphenicol acetyltransferese (CAT) coding sequence, we analyzed CAT expression in various tissues (brain, lung, liver, kidney, spleen) in these transgenic rats. We found that the ECAT gene, which has sufficient of the upstream regulatory region (approx. 2.9 kb) of the gene containing GPEI, is trans-activated in the kidney and lung of transgenic rats in a similar manner to endogenous GST-P. When either the GPEI core sequence or the AP-1 site near the promoter is deleted, CAT expression decreases to almost background level. Substitution of the GPEI core or the AP-1 site near the promoter to this silent construct (5CATGPEIcore) reconstituted CAT expression in the transgenic rats. In these rats, CAT was expressed in the brain and lung rather than in the kidney, showing a somewhat different pattern from the endogenous GST-P. In the brain tissue of the 5CATGPEIcore transgenic rat, CAT was demonstrated in the glia cells, which is consistent with endogenous GST-P expression. These results suggest that a relatively long upstream region (approx. 2.9 kb) is required for tissue-specific expression of the GST-P gene and that GST-P expression in the brain may be regulated differently from its expression in other organs. [ABSTRACT FROM AUTHOR]