THE UPSTREAM REGULATORY REGIONS OF THE HEPATOCYTE GROWTH-FACTOR GENE PROMOTER ARE ESSENTIAL FOR ITS EXPRESSION IN TRANSGENIC MICE

To understand the molecular mechanisms of hepatocyte growth factor (HG F) gene transcription in vivo, we report the generation and characteri zation of transgenic mice harboring various lengths of the mouse HGF p romoter linked to the chloramphenicol acetyltransferase reporter gene. Analysis of different tissues of the transgenic mouse lines having th e 2.7-kilobase (kb) promoter construct revealed a pattern of reporter gene expression in embryonic and adult tissues that paralleled that of endogenous HGF gene expression. A similar expression pattern was obse rved in the 0.7-kb transgenic lines. However, in contrast to in vitro data, no promoter activity was detected in four independent transgenic lines harboring the 0.1-kb construct. Akin to the activity of the end ogenous HGF gene, which is induced in the liver, lung, and spleen in r esponse to 70% partial hepatectomy, the reporter gene driven by the 2. 7-kb promoter construct was strongly induced, whereas that driven by t he 0.7-kb promoter construct was modestly induced in these organs afte r partial hepatectomy. Together, these data suggest that the region be tween -0.1 and -0.7 kb of the HGF gene promoter is essential to drive its expression in vivo and that additional upstream sequences located between -0.7 and -2.7 kb are also necessary for its maximum inducibili ty in response to cues that stimulate tissue growth and regeneration.