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Regulation of IAPP transcription by spliced XBP1 Lin, Susan


In Alzheimer’s disease (AD), progressive memory loss and cognitive decline have been associated with the presence of extracellular amyloid plaques in the brain. These plaques are primarily composed of aggregated amyloid-beta, but may contain other types of amyloid species such as islet amyloid polypeptide (IAPP). Aggregated IAPP forms the islet amyloid found in 90% of type II diabetes mellitus (T2DM) patients, and IAPP can readily cross the blood brain barrier to enter the central nervous system. With substantial epidemiological evidence suggesting that T2DM can significantly increase the risk of developing AD, IAPP has been proposed to be a potential link between the two diseases. Currently, the mechanisms underlying IAPP aggregation unclear, but factors such as IAPP overexpression and impaired processing have been implicated in its toxicity. Given the sensitivity of pancreatic islet cells to endoplasmic reticulum (ER) stress, we hypothesized that ER stress in T2DM may disrupt IAPP cellular homeostasis by affecting its synthesis. We investigated the transcriptional regulation of IAPP by cloning a 1618 base pair 5’ flanking region of the human IAPP (hIAPP) promoter and analyzed its promoter activity (along with shorter deletion constructs) in beta- and non-beta-cell lines. Tunicamycin-induced ER stress significantly enhanced hIAPP promoter activity and transcript levels in a human beta-cell line via activating X-box binding protein 1 (XBP1) splicing. We further identified a binding site for spliced XBP1 on the hIAPP promoter, and abolishing this binding site by substitution or deletion mutagenesis significantly diminishes the effects of ER stress on hIAPP promoter activity. Our study uncovers a link between ER stress and IAPP at the transcriptional level, and provides novel insight into the role of ER stress in IAPP cytotoxicity during T2DM and ultimately, AD.

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