IDENTIFICATION OF AN ENHANCER RESPONSIBLE FOR TUMOR-MARKER GENE-EXPRESSION BY MEANS OF TRANSGENIC RATS

The glutathione transferase P (GST-P) gene is known for its specific e xpression during chemical hepatocarcinogenesis of the rat and is used as a tumor marker for hepatocellular carcinoma. We have shown recently that the upstream 2.9-kb region of the GST-P gene is sufficient for c onferring tumor-specific expression of the gene in vivo (S. Morimura e t al., Proc. Natl. Acad. Sci. USA, 90: 2065-2068, 1993). To further id entify crucial sequence elements regulating the unique expression of t his gene, we have established six independent lines of transgenic rats bearing distinct areas of the GST-P gene that are connected to the ch loramphenicol acetyltransferase coding region and analyzed changes of the chloramphenicol acetyltransferase activity during the course of ch emical hepatocarcinogenesis. We demonstrate here that the enhancer, gl utathione transferase P enhancer I, that is located 2.5 kb upstream of the GST-P gene is required and sufficient for its tumor-specific expr ession of the. gene among other controlling elements. This approach to transgene expression could be used to define other enhancers, the act ivity of which is dependent on cellular changes such as carcinogenesis , development, and differentiation.