Transcriptional regulation of the endoplasmic reticulum stress gene chop in pancreatic insulin-producing cells.
Diabetes
; 56(4): 1069-77, 2007 Apr.
Article
em En
| MEDLINE
| ID: mdl-17395747
ABSTRACT
Endoplasmic reticulum stress-mediated apoptosis may play an important role in the destruction of pancreatic beta-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-1beta + interferon-gamma, the free fatty acid palmitate, and the sarcoendoplasmic reticulum pump Ca(2+) 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 eIF2alpha 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 beta-cells to diverse endoplasmic reticulum stress inducers, leading to a differential regulation of Chop transcription.
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Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
/
Regulação da Expressão Gênica
/
Retículo Endoplasmático
/
Células Secretoras de Insulina
/
Fator de Transcrição CHOP
/
Insulina
Limite:
Animals
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article