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Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing Cells

¹ Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
² Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
³ Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee

Address correspondence and reprint requests to Dr. Alessandra K. Cardozo, Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808-CP-618, 1070 Brussels, Belgium. E-mail: akupperc{at}ulb.ac.be

Abbreviations: ATF, activating transcription factor; C/EBP, CCAAT/enhancer binding protein; Chop, C/EBP homologous protein; CPA, cyclopiazonic acid; EMSA, electrophoretic mobility shift assay; ERSE, endoplasmic reticulum stress response element; FFA, free fatty acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun NH₂-terminal kinase; PERK, PKR-like endoplasmic reticulum kinase; PMSF, phenylmethylsulfonyl fluoride; SERCA, sarcoendoplasmic reticulum pump Ca²⁺ ATPase; UPR, unfolded protein response

Endoplasmic reticulum stress–mediated apoptosis may play an important role in the destruction of pancreatic ß-cells, thus contributing to the development of type 1 and type 2 diabetes. One of the regulators of endoplasmic reticulum stress–mediated cell death is the CCAAT/enhancer binding protein (C/EBP) homologous protein (Chop). We presently studied the molecular regulation of Chop expression in insulin-producing cells (INS-1E) in response to three pro-apoptotic and endoplasmic reticulum stress–inducing agents, namely the cytokines interleukin-1ß + interferon-, the free fatty acid palmitate, and the sarcoendoplasmic reticulum pump Ca²⁺ ATPase blocker cyclopiazonic acid (CPA). Detailed mutagenesis studies of the Chop promoter showed differential regulation of Chop transcription by CPA, cytokines, and palmitate. Whereas palmitate- and cytokine-induced Chop expression was mediated via a C/EBP–activating transcription factor (ATF) composite and AP-1 binding sites, CPA induction required the C/EBP-ATF site and the endoplasmic reticulum stress response element. Cytokines, palmitate, and CPA induced eIF2 phosphorylation in INS-1E cells leading to activation of the transcription factor ATF4. Chop transcription in response to cytokines and palmitate depends on the binding of ATF4 and AP-1 to the Chop promoter, but distinct AP-1 dimers were formed by cytokines and palmitate. These results suggest a differential response of ß-cells to diverse endoplasmic reticulum stress inducers, leading to a differential regulation of Chop transcription.

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