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J. Biol. Chem., Vol. 279, Issue 27, 27948-27956, July 2, 2004

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Human CCAAT/Enhancer-binding Protein Gene Expression Is Activated by Endoplasmic Reticulum Stress through an Unfolded Protein Response Element Downstream of the Protein Coding Sequence^*

Chin Chen, Elizabeth E. Dudenhausen, Yuan-Xiang Pan, Can Zhong, and Michael S. Kilberg

From the Department of Biochemistry and Molecular Biology, Center for Mammalian Genetics, and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, Florida 32610-0245

CCAAT/enhancer-binding protein (C/EBP) is a member of the bZIP family of transcription factors that contribute to the regulation of a wide range of important cellular processes. The data in the present study document that transcription from the human C/EBP gene is induced in response to endoplasmic reticulum stress, such as glucose deprivation, or treatment of cells with tunicamycin or thapsigargin. Transient transfection of C/EBP genomic fragments linked to a luciferase reporter gene demonstrated that the C/EBP promoter plays no major regulatory role. Instead, by deletion analysis it was discovered that a 46-bp region, located at a genomic site that corresponds to the 3'-untranslated region of the C/EBP mRNA, harbored an element that was required for the stress response. Mutagenesis demonstrated that a cis-regulatory element located at nt +1614–1621 (5'-TGACGCAA-3') is responsible for activation of the C/EBP gene. Electrophoresis mobility shift analysis revealed that proteins are bound to this element and that the amount of binding is increased following glucose deprivation. This element is homologous to a previously reported mammalian unfolded protein response element that binds XBP-1. Consistent with those data, overexpression of XBP-1 caused an increase in transcription that was mediated by the C/EBP mammalian unfolded protein response element.

Received for publication, December 19, 2003 , and in revised form, April 14, 2004.

^* This work was supported by NIDDK, National Institutes of Health, Grants DK-59315 and DK-52064 (to M. S. K.). 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.

To whom correspondence and reprint requests should be addressed: Dept. of Biochemistry and Molecular Biology, University of Florida College of Medicine, Box 100245, Gainesville, FL 32610-0245. Tel.: 352-392-2711; Fax: 352-392-6511; E-mail: mkilberg{at}ufl.edu.

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