It is proposed to use mouse salivary glands as an in vivo model to corroborate the hypothesis that proto-oncogenes play key roles in the regulation of differentiation and cell proliferation. To this end, we will analyze the expression of c-fos, c-myc, c-ras-Ki, and c-ras-Ha by measuring steady state levels of their transcripts by Northern and dot blot hybridization, transcriptional activities by nuclear run-off assays, the cellular population in which c-onc mRNAs are located by in situ hybridization, and the expression and location of c-onc proteins in salivary glands of the mouse by immunocytochemical methods. We will correlate c-onc expression with differentiation of the acinar cells in the parotid gland, quantitated by measuring the expression of the yield-amylase gene, with normal and isoproterenol-induced cell replication, and hyperplastic/hypertrophic growth produced by the chronic adminsitration of IPR. In preliminary experiments we have observed an early stimulation of c-fos expression by IPR. We propose to test the hypothesis that isoproterenol-induced c-fos expression in the salivary glands is mediated by cyclic AMP, and is independent of the secretory response of the acinar cells to IPR and other drugs.
