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J. Biol. Chem., Vol. 283, Issue 33, 22443-22456, August 15, 2008

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Differential Control of the CCAAT/Enhancer-binding Protein β (C/EBPβ) Products Liver-enriched Transcriptional Activating Protein (LAP) and Liver-enriched Transcriptional Inhibitory Protein (LIP) and the Regulation of Gene Expression during the Response to Endoplasmic Reticulum Stress^*

Yi Li, Elena Bevilacqua, Calin-Bogdan Chiribau, Mithu Majumder, Chuanping Wang, Colleen M. Croniger, Martin D. Snider, Peter F. Johnson^¶, and Maria Hatzoglou¹

From the Departments of Nutrition and Biochemistry, School of Medicine, Case Western University, Cleveland, Ohio 44106-4954 and ^¶Basic Research Laboratory, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers a stress response program that protects cells early in the response and can lead to apoptosis during prolonged stress. The basic leucine zipper transcription factor, CCAAT/enhancer-binding protein β (C/EBPβ), is one of the genes with increased expression during ER stress. Translation of the C/EBPβ mRNA from different initiation codons leads to the synthesis of two transcriptional activators (LAP-1 and -2) and a transcriptional repressor (LIP). The LIP/LAP ratio is a critical factor in C/EBPβ-mediated gene transcription. It is shown here that the LIP/LAP ratio decreased by 5-fold during the early phase of ER stress and increased by 20-fold during the late phase, mostly because of changes in LIP levels. The early decrease in LIP required degradation via the proteasome pathway and phosphorylation of the translation initiation factor, eIF2. The increased LIP levels during the late phase were due to increased synthesis and increased stability of the protein. It is proposed that regulation of synthesis and degradation rates during ER stress controls the LIP/LAP ratio. The importance of C/EBPβ in the ER-stress response program was demonstrated using C/EBPβ-deficient mouse embryonic fibroblasts. It is shown that C/EBPβ attenuates expression of pro-survival ATF4 target genes in late ER stress and enhances expression of cell death-associated genes downstream of CHOP. The inhibitory effect of LIP on ATF4-induced transcription was demonstrated for the cat-1 amino acid transporter gene. We conclude that regulation of LIP/LAP ratios during ER stress is a novel mechanism for modulating the cellular stress response.

Received for publication, February 8, 2008 , and in revised form, May 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK060596, DK053307 (to M. H.), and DK075040 (to C. M. C.) and by National Institutes of Health Intramural Research Program of the Center for Cancer Research, NCI (to P. J.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table I.

¹ To whom correspondence should be addressed: Dept. of Nutrition, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4954. Tel.: 216-368-3012; E-mail: mxh8{at}case.edu.

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