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

  1. Pierre Pirot1,
  2. Fernanda Ortis1,
  3. Miriam Cnop12,
  4. Yanjun Ma3,
  5. Linda M. Hendershot3,
  6. Décio L. Eizirik1 and
  7. Alessandra K. Cardozo1
  1. 1Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
  2. 2Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
  3. 3Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
  1. 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

Abstract

Endoplasmic reticulum stress–mediated apoptosis may play an important role in the destruction of pancreatic β-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-1β + interferon-γ, 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 eIF2α 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 β-cells to diverse endoplasmic reticulum stress inducers, leading to a differential regulation of Chop transcription.

Footnotes

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1253.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted December 23, 2006.
    • Received September 6, 2006.
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