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Differential control of the CCAAT/enhancer-binding protein beta (C/EBPbeta) 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.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2008 Aug 15; Vol. 283 (33), pp. 22443-56. Date of Electronic Publication: 2008 Jun 11. - Publication Year :
- 2008
-
Abstract
- 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 beta (C/EBPbeta), is one of the genes with increased expression during ER stress. Translation of the C/EBPbeta 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/EBPbeta-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, eIF2alpha. 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/EBPbeta in the ER-stress response program was demonstrated using C/EBPbeta-deficient mouse embryonic fibroblasts. It is shown that C/EBPbeta 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.
- Subjects :
- Animals
CCAAT-Enhancer-Binding Protein-beta deficiency
CCAAT-Enhancer-Binding Protein-beta genetics
Cell Line, Tumor
Genes, Reporter
Glioma genetics
Luciferases genetics
Plasmids
RNA, Neoplasm genetics
RNA, Neoplasm isolation & purification
Rats
CCAAT-Enhancer-Binding Protein-beta physiology
Endoplasmic Reticulum physiology
Liver physiology
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 283
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18550528
- Full Text :
- https://doi.org/10.1074/jbc.M801046200