Chronic injections of the beta-adrenergic agonist, isoproterenol, produce, in addition to cell hypertrophy and hyperplasia, biochemical alterations in protein synthesis in the rat parotid gland. Among the biochemical changes is an increase in specific activity for an enzyme normally thought of as a Golgi membrane marker enzyme 4beta-galactosyltransferase. This change in activity is accompanied by an altered subcellular localization of this enzyme to the plasma membrane. A similar change in enzyme activity and localization is observed with the introduction of dietary changes that result in increased functional gland activity and certain drug regimens that block cAMP degradation (caffeine and theophylline). The importance of the up-regulation and surface localization of 4beta-galactosyltransferase became apparent in experiments in which agents that interact with this enzyme were shown to severely inhibit parotid gland cell hypertrophy from taking place either in vivo or in vitro. Numerous reports have shown that alteration of cell-surface galactosyltransferase activity might be involved in cell adhesion, differentiation, and tumorogenesis. We therefore believe that studies of the regulation of the transferase are curcial to understanding growth control in parotid and other tissues. The study of gene regulation for this enzyme will be accomplished through the use of cDNA clones to galactosyltransferase recently isolated in my laboratory. The cDNA clone, in addition, has been used to isolate genomic DNA coding for this enzyme. The organization of the transferase gene will be examined by DNA sequence analysis. Using a combination of deletion mutants we will confirm the functional boundaries of sequences involved with active transcription of the gene. The 4beta-galactosyltransferase cDNA clone will allow us to examine, at a molecular level, the effects that gene expression and cell-surface expression of this enzyme have on parotid acinar cell growth in vivo and in vitro. The role of 4beta-galactosyltransferase in mediating gland hypertrophy will also be expanded to include other physiological conditions leading to tissue hyperplasia and hypertrophy in the rat. These findings will be used to evaluate preliminarily the contribution of 4beta-galactosyltransferase in human pathologies of the oral cavity, in particular disorders of salivary glands involving tissue hypertrophy.
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