The long term goal of this proposal is to gain a detailed understanding of regulatory networks which control cell proliferation, how these networks are perturbed during initiation and progression of neoplastic growth, and how genetic factors influence these perturbations. To this end, the proposal is centered on analysis of liver tumorigenesis in transgenic mice containing mouse major urinary protein (MUP) enhancer/promoter fusion constructs. The well defined and relatively late postnatal activation of this promoter in the liver, and the potential androgen conditional expression provide a novel method for analysis of tumorigenesis. These transgenic mice will be used to investigate the timing and phasing of tumorigenesis relative to initiation of oncogene expression, whether continual expression of the oncogene (transgene) is necessary for tumorigenesis and analysis of changes in liver gene expression which occur during specific stages of liver tumorigenesis. This proposal also focuses on analysis of genetic determinants which influence susceptibility to spontaneous and chemically induced liver carcinogenesis and whether transgenic models of liver tumorigenesis respond to these determinants.