Chronic administration of the beta-adrenergic agonist isoproterenol induces parotid gland hypertrophy and hyperplasia in the rat. This serves as a useful model for studying the physiological and biochemical alterations that occur in cell proliferation. An important event noted in the isoproterenol induced parotid acinar cell hyperplasia is the increase in cell surface 4 betagalactosyltransferase (Gal Tase). Numerous studies have shown that alterations in cell surface Gal Tase may be involved in cell-cell interaction during embryogenesis, differentiation and tumorigenesis. The elevated surface Gal Tase in parotid acinar cells then appears to interact with the EGF-R in a manner similar to growth factor associated 'receptor-ligand' interaction. It is believed that the EGF-R undergoes conformational changes in its carbohydrate moieties so as to serve as a substrate for cell surface-localized Gal Tase. However, it is not clear how the signal produced by such an interaction reaches the nucleus to modulate the processes such as DNA replication and gene expression. I therefore propose to examine the involvement of second messengers, and receptor crosstalk produced during the regulation of acinar cell growth. To accomplish this, phosphoinositol metabolism (along with their specific metabolic kinases), and adenylate cyclase G activating protein (GAP activity), will be studied in both the control and ISO stimulated parotid glands. Parallel studies with EGF and Gal Tase stimulation will be conducted to determine the extent of Gal Tase's ability to mimic EGF in regulating this specific receptor response. In addition, the characterization of the carbohydrate structure of EGF-R in the control and ISO-treated rat parotid gland will be made to confirm the unique Gal Tase - EGF-R interaction which appears to be a primary event in beta-agonist mediated signal transduction for proliferation. The injection of antibody to either Gal Tase or the EGF-R, along with ISO, have been shown to prevent acinar cell proliferation. The carbohydrate changes of the receptor may provide insights into the regulation and re-expression of fetal carbohydrate structures during parotid acinar cell hyperplasia. While not neoplastic, the expression of fetal carbohydrate antigens by these cells may reflect a common hallmark of transformed cells; namely a renewed synthesis of fetal developmental carbohydrate markers on the cell surface. These findings on the regulation of acinar cell signal transduction pathways in the isoproterenol induced parotid gland hyperplasia may be helpful in evaluating potential new treatments for the control of cell proliferation in human pathologies in general and those in particular of the oral cavity and soft tissue.
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