The overall goal of this second revision of a FIRST Award application is to characterize the tissue-specific regulation of the c-myc protooncogene using liver regeneration as a model of normal cellular proliferation. Preliminary evidence by the investigator suggests that transcription initiation of c-myc mRNA in liver and kidney following partial hepatectomy proceeds using different c-myc transcription start sites in a tissue-specific manner. Dr. Jones has also developed transgenic mouse lines which express beta-galactosidase (b-gal) under control of the human c-myc promoter and has performed pilot experiments on up-regulation of b-gal expression in kidney tissue following partial hepatectomy in c-myc/lacZ transgenic mice.
The specific aims of the current project are: 1) to characterize tissue-specific c-myc promoter utilization following partial hepatectomy using regenerating liver as a model of normal cellular proliferation; 2) to analyze tissue-specific c-myc promoter utilization in transgenic mouse lines containing the human c-myc minimal promoter region directing expression of b-gal; and 3) to characterize the functional contribution of other c-myc regulatory regions in the tissue-specific up-regulation of c-myc promoter-driven expression of b-gal and c-myc promoter utilization following partial hepatectomy in transgenic mice. These studies are intended to elucidate the molecular mechanism(s) and DNA regulatory events which govern the tissue-specific expression of the c-myc protooncogene following a proliferative stimulus in vivo.
