Mammalian salivary glands produce secretions that initiate digestion and bathe and protect the oral cavity. Salivary cystatins, proteins secreted by the submandibular and parotid glands, are believed to play a major role in this protection. Cystatins are evolutionarily conserved, naturally occurring cysteine proteinase inhibitors that regulate proteolysis by endogenous cysteine proteinases, as well as by proteinases of microbial pathogens and of some viruses. Although cystatins inhibit cysteine proteinases in vitro, their in vivo functions have not been delineated in detail. Since our long-term goal is to understand the role of cystatins in growth, differentiation, morphogenesis, and function of salivary glands, we propose to examine mechanisms governing expression of the cystatin S gene, which is expressed in rat salivary glands. This proposal will elaborate upon our previous findings that the cystatin S gene is unique in that it is cell type-and salivary gland-specific, it is expressed at a specific stage of posnatal development of the submandibular gland, it is turned off in adult animals, and it can be induced in adult rats by beta-receptor mediated mechanisms. In addition, its 5' flanking sequence has three sequence elements (I, II, and III) that are common to salivary gland-specific genes, and inserted between conserved elements II and III is a GT rich region (GT rich regions are thought to either inhibit or increase transcriptional activity of specific genes). Two major or hypotheses to be tested are that: 1) the conserved sequence elements present in all salivary gland-specific genes are the genetic elements that dictate salivary gland-specific phenotype, and 2) these conserved sequence elements somehow participate in the beta-adrenergic modulation of expression of a salivary gland-specific gene, cystatin S.
Our specific aims are to: 1. determine the role of the conserved salivary gland-specific DNA sequence elements in cells in culture 2. identify and delineate potential regulatory elements In the cystatin S promoter that mediate IPR-induced cystatin S gene expression 3. verify that the cis-acting conserved salivary gland-specific regulatory elements, and the regulatory elements that mediate IPR-induced cystatin S gene expression, that were identified in tissue culture act in vivo using transgenic mice 4. determine whether there are changes in trans-acting factors that accompany changes in expression of the cystatin S gene
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