Saliva is critical for the maintenance of oral function and health. Patients with radiation for head and neck cancer and with Sjogren's syndrome suffer irreversible damage to salivary glands, rendering them atrophic. The long-term goal of this project is to elucidate the cellular and molecular mechanisms, in particular protein modifications, involved in salivary adaptive responses. Protein modifications by the ubiquitin homologue, SUMO, and phosphorylation have been identified as important regulatory mechanisms governing transcription, DMA repair, cell cycle progression, and intracellular trafficking. This application will focus on the crosstalk and individual roles of SUMOylation-dependent and protein kinase C5 (PKC8)-mediated signaling network in conveying resistance and sensitivity, respectively, towards hypoxia-induced injury in salivary cells. Cellular hypoxia is a stress with important implications in the developmental biology, normal physiology, and many pathological conditions, including a myriad of acute and chronic disease states and cancers. Emerging evidence suggests that hypoxia regulates biological and biochemical functions in many different cell types, yet, the mechanisms by which salivary cells utilize to counteract or reinforce hypoxia-induced cell/DMA damage and growth inhibition are still not clear. We recently demonstrated that hypoxia leads to an increase in SUMOylation in salivary Pa-4 cells, which results in an enhanced NF-tcB-mediated transactivation and an attenuation of PKC8/caspase-3 activation, suggesting that SUMO-dependent protein-protein interaction plays an essential role in modulating salivary hypoxic responses. Further, hypoxia-induced salivary adaptive responses also appear to involve the phosphatidylinositol kinase-related kinase (PIKK) family members, such as ataxia telangiectasia mutate (ATM), implicating that hypoxia leads to cumulative DMA damage, rendering either cell survival or growth inhibition. Therefore, we hypothesize that salivary epithelial adaptive responses against hypoxia is mediated, at least in part, by an intricate balance among ATM activation, SUMO-dependent protein- protein interaction and its associated signaling, and PKC8 activation. To test our hypothesis, we propose the following three Specific Aims: 1) To establish the role of SUMO-dependent protein modification in protecting salivary epithelial cells against hypoxia-induced injury; 2) To investigate SUMOylation-dependent and PKC5-mediated signaling network crosstalk upon hypoxic exposure and delineate the antagonistic role by PKC8-activation in programming SUMOylation-promoted hypoxia tolerance in salivary epithelial cells; and 3) To characterize SUMOylation targets that mediate the adaptive responses to hypoxia in salivary epithelial cells. The proposed mechanistic studies will extend our current knowledge on hypoxia-elicited pathogenesis in salivary glands. Information obtained from this study should lead to the development of innovative prevention and therapeutic approach against pathological manifestations in salivary glands, associated with Sjogren's syndrome and head and neck irradiation. ? ? ?
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