The unfolded protein response (UPR) is an intracellular signaling pathway that connects the endoplasmic reticulum (ER) to the transcription activation in the nucleus a set of genes with protein folding function. Among these, the 78 kDa glucose regulated protein GRP78 (also identified as BiP) has been examined most vigorously as a model system for the mammalian UPR. This proposal is aimed at continuing our investigation into the mechanisms and pathways for the stress induction of the grp78 promoter in mammalian cells, and the physiological significance of GRP78 induction in vivo. GRP78 is an essential calcium- binding molecular chaperone localized in the ER. Disruption of GRP78 regulation and function has been implicated in human diseases resulting from ER stress and formation of malfolded protein. Further, the level of GRP78 is elevated in transformed cells and solid tumors, suggesting that the anti-apoptotic function of GRP78 may be usurped to enhance their resistance against immune surveillance, leading to induction in vivo. Based on detailed analysis of the grp78 promoter, we have uncovered a genetic code CCAAT(N9)CCACG referred to as the endoplasmic reticulum stress element (ERSE) for its stress induction and complex synergistic interaction interactions among constitutive and stress-induced activators. The proposed studies will characterize the newly discovered regulators of grp78 stress induction, their link to the basal transcription machinery and their relationship to the different pathways revolved uncovered for ER to nucleus signaling. Further, the significance of chromosome remodeling in grp78 induction will be examined. The hypothesis to be tested is that upon ER stress the chromatin structure of the mammalian grp78 promoter undergoes changes.,. This allows a complex array of DNA binding proteins (NF-Y, YY1, TFII-I and mammalian Hac1) and other transcription factors and co-factors (ATF6, p300) that act through protein-protein interaction to activate the grp78 promoter. We further propose that specific post-translational modifications of the activators induced by ER-stress may integrate stress signal transduction with transcription. With the link of GRP78 induction to tumorigenesis, drug resistance and Alzheimer's disease, fundamental knowledge in the novel regulatory circuitry of grp78 will provide the basis to devise new therapy against cancer and other human diseases by targeting its regulatory components and pathways.
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