Pharmacological Reviews Get Tables of Contents delivered automatically
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     


0031-6997/04/5602-291-330$7.00
Pharmacol Rev 56:291-330, 2004

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schrem, H.
Right arrow Articles by Borlak, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schrem, H.
Right arrow Articles by Borlak, J.

Article

Liver-Enriched Transcription Factors in Liver Function and Development. Part II: the C/EBPs and D Site-Binding Protein in Cell Cycle Control, Carcinogenesis, Circadian Gene Regulation, Liver Regeneration, Apoptosis, and Liver-Specific Gene Regulation

Harald Schrem, Jürgen Klempnauer and Jürgen Borlak

Viszeral- und Transplantationschirurgie, Medizinische Hochschule, Hannover, Germany (H.S., J.K.); and Center of Drug Research and Medical Biotechnology, Fraunhofer Institut für Toxikologie und Experimentelle Medizin, Hannover, Germany (J.B.)

Abstract
I. Introduction
II. The CAAT/Enhancer-Binding Proteins
    A. The C/EBP Subfamily of the Basic Region Leucine Zipper Family of Transcription Factors
        1. C/EBP Homo- and Heterodimers.
        2. C/EBPs and Cross-Talk with Other Transcription Factors.
        3. Sumoylation May Modulate the Transactivation Activity of C/EBPs.
    B. C/EBP-{alpha} (Originally Named C/EBP)
        1. The Single-Exon C/EBP-{alpha} Gene Is Highly Conserved in Different Species.
        2. Tissue-Specific and Species-Specific Autoregulation of the C/EBP-{alpha} Promoter.
        3. Thyroid Hormone Positively Regulates C/EBP-{alpha} Expression.
        4. Possible Regulatory Function of Alternative C/EBP-{alpha} Translation Products.
        5. The Transactivation Domains of C/EBP-{alpha}.
        6. RFC140 Acts as a Coactivator for C/EBP-{alpha}.
        7. CAAT Displacement Protein as a Competitive Repressor for C/EBP-{alpha}-Mediated Transactivation.
        8. Translational Inhibition of C/EBP-{alpha} Expression by Calreticulin.
    C. C/EBP-{beta} (Formerly Also Named Liver-Activating Protein, Interleukin 6DBP, CRP2, or Nuclear Factor Interleukin 6)
        1. C/EBP-{beta} Isoforms Are the Result of Alternative Translation Initiation.
        2. Liver-Specific Proteosomal Regulation of C/EBP-{beta} Isoforms by C/EBP-{alpha}.
        3. Translational Regulation of C/EBP-{beta} Isoforms by CUGBP1.
        4. Translational Inhibition of C/EBP-{beta} Expression by Calreticulin.
        5. Regulation of the C/EBP-{beta} Promoter.
        6. Tissue-Specific Autoregulation of C/EBP-{beta} Transcription.
        7. Negative Regulatory Domains of C/EBP-{beta}.
        8. Post-translational Phosphorylation of C/EBP-{beta}.
        9. Phosphorylation of C/EBP-{beta} Ser239 leads to C/EBP-{beta} Nuclear Export.
        10. Phosphorylation of C/EBP-{beta} Thr217 by p90 Ribosomal S Kinase.
    D. C/EBP-{gamma} (Also Called Ig/EBP)
        1. Structure and Chromosomal Location of C/EBP- {gamma}.
    E. C/EBP-{delta}
        1. Chromosomal Localization.
        2. Transcriptional Induction of C/EBP-{delta} by Interleukin 6.
        3. Regulation of C/EBP-{delta} by Phosphorylation.
        4. Autoregulation of C/EBP-{delta}.
        5. Inhibition of C/EBP-{delta} Gene Expression by C/EBP-{beta} and C/EBP-{zeta}.
    F. C/EBP-{zeta} (Also Called GADD153 or CHOP-10)
        1. C/EBP-{zeta} as a Dominant Negative Regulator of C/EBPs.
        2. Chromosomal Localization and Characteristics of the Promoter of C/EBP-{zeta}.
        3. Regulation of C/EBP-{zeta} in Response to Oxidative Stress and DNA Damage.
        4. Phosphorylation of C/EBP-{zeta}.
        5. Autoregulation of GADD153 Expression.
        6. Differential Regulation of C/EBP-{zeta}
        7. C/EBP-{zeta}-C/EBP-{beta} Heterodimer-Mediated Gene Regulation.
    G. Hormones, Metabolic Hepatic Functions, and the C/EBPs
        1. C/EBP-{alpha} and Energy Metabolism.
        2. C/EBP-{alpha} in Gluconeogenesis and Detoxification of Ammonia and Bilirubin.
        3. C/EBP-{beta} and Energy Metabolism.
        4. Insulin and Glucocorticoids Regulate Gluconeogenesis via C/EBP-{beta} Isoforms.
        5. Thyroid Hormone and Retinoic Acid Regulate C/EBP-{alpha} and -{beta} in the Liver.
        6. The C/EBPs and the Growth Hormone-Regulated Network of Transcription Factors.
        7. C/EBPs and the Control of Cytochrome P450 Gene Expression.
    H. The Role of C/EBPs in the Acute Phase Response
        1. Differential Expression Patterns of the C/EBPs during the Acute Phase Response.
        2. Differential Expression of C/EBP-{alpha} and C/EBP-{beta} Isoforms.
        3. Acute Phase Response-Related mRNA/Protein Interaction leads to Liver-Enriched Transcriptional Inhibitory Protein Translation.
        4. Increased Liver-Enriched Transcriptional Inhibitory Protein Translation Leads to Reduced C/EBP-{alpha} RNA Levels.
        5. Tumor Necrosis Factor {alpha}-Mediated Post-translational Regulation of C/EBPs.
        6. Interleukin 6-Mediated Post-translational Phosphorylation of C/EBP-{beta}.
        7. Influence of Interleukin 6 on C/EBP-{beta} Transcription.
        8. Transcriptional Induction of C/EBP-{delta} after Interleukin 6 Stimulus.
        9. A Pivotal Role for C/EBP-{alpha} in the Acute Phase Response.
        10. Interactions of C/EBP-{alpha} and C/EBP-{beta} with the Nuclear Matrix.
        11. Protein/Protein Interaction between Nuclear Factor {kappa}B p65 and C/EBP-{beta}.
        12. Nucleolin Is an Antagonist to C/EBP-{beta} in the Acute Phase Response.
        13. Nuclear Factor {kappa}B and Nopp140 Act as Coactivators for C/EBP-{beta}.
        14. Heterogeneous Nuclear Ribonucleoprotein K as a Negative Regulator of C/EBP-{beta}-Mediated Gene Activation.
        15. The Role of the Hypothalamic-Pituitary-Adrenal Axis in the Acute Phase Response.
    I. C/EBPs and Cell Cycle Control
        1. C/EBP-{alpha} Expression and Growth Arrest.
        2. The Glucocorticoid-Induced G1 Cell Cycle Arrest Is Mediated by C/EBP-{alpha}.
        3. Protein/Protein Interactions among p21, cdk2, cdk4, and C/EBP-{alpha}.
        4. C/EBP-{alpha} and p107 Protein/Protein Interaction Disrupts E2F Complexes.
        5. C/EBP-{beta} Arrests the Cell Cycle before the G1/S Boundary.
        6. Transforming Growth Factor {alpha}-Mediated Phosphorylation of C/EBP-{beta} Leads to Hepatocyte Proliferation.
    J. C/EBPS and Cellular Differentiation
        1. Transcription Factors during Liver Development and Oval Cell Differentiation.
        2. Transdifferentiation of Pancreas to Liver and C/EBP-{beta} Induction.
    K. C/EBPs and Apoptosis
        1. Tumor Necrosis Factor {alpha}-Mediated Apoptosis and C/EBP-{beta}.
        2. Fas-Induced Apoptosis and C/EBP-{beta}.
    L. The Role of C/EBPs in Development
        1. Differential Regulation of C/EBPs and Their Isoforms during Development.
        2. C/EBP-{alpha} and the Developmental Expression of Essential Metabolic Genes.
        3. Differential CYP3A7 and CYP3A4 Expression during Development.
        4. Hepatic Expression of the Rat CYP2D5 Gene Is Regulated by C/EBP-{beta}.
    M. The Role of C/EBPs in Liver Regeneration
        1. Liver Regeneration after Concanavalin A-Induced Liver Injury.
        2. Hepatocyte Growth Factor Stimulates C/EBP-{beta} and Nuclear Factor {kappa}B Expression.
        4. Transcriptional Regulation of C/EBP-{alpha} in Liver Regeneration.
        5. C/EBP-{beta} Isoforms in Liver Regeneration.
        6. C/EBP-{alpha} and C/EBP-{beta} Expression after Partial Hepatectomy.
        7. Influence of Age on Liver Regeneration.
        8. Influence of Obstructive Jaundice on Liver Regeneration.
        9. Cyclooxygenase 2 Contributes to Liver Regeneration.
    N. C/EBPs and their Role in Liver Tumor Biology
        1. The Ratio of C/EBP-{alpha} and C/EBP-{beta} Expression in Chemical Carcinogenesis.
        2. Protein/Protein Interaction between Mutant p53 and C/EBP-{beta} in Liver Cancer.
        3. Regulatory Role of Liver-Enriched Transcription Factors in Liver Cancer.
        4. Repression of C/EBP-{alpha}-Mediated Transactivation by CAAT Displacement Protein in Human Liver Cancer?
    O. Human Disease with Causative C/EBP Involvement
        1. Essential Hypertension in African-Americans.
III The D Site-Binding Protein
    A. Chromosomal Localization and Interspecies Conservation
    B. Genomic Structure of D Site-Binding Protein
    C. The Transactivation Domain of D Site-Binding Protein
    D. Cotranscriptional and Post-transcriptional Splicing of D Site-Binding Protein
    E. The Proline and Acidic-Rich Domain and the p300 Coactivator Are Involved in Transactivation by D Site-Binding Protein
    F. D Site-Binding Protein Forms Homo- and Heterodimers with Proline and Acidic-Rich Protein Family Members
    G. The Rhythm of D Site-Binding Protein Expression Beats the Drum for Circadian Gene Regulation
    H. Regulation of the D Site-Binding Protein Promoter by CLOCK
    I. Changes of Feeding Times Influence Circadian D Site-Binding Protein Expression Patterns
    J. Influence of Glucocorticoids on Hepatic Circadian Gene Expression
    K. Rat CYP2C6 Expression in Development Is Positively Regulated by D Site-Binding Protein
    L. Circadian Expression of Rat CYP7 Is Positively Regulated by D Site-Binding Protein
IV. Toxicogenomics as an Emerging Science in Toxicology
V. Conclusion
Abstract

In the first part of our review (see Pharmacol Rev 2002;54:129-158), we discussed the basic principles of gene transcription and the complex interactions within the network of hepatocyte nuclear factors, coactivators, ligands, and corepressors in targeted liver-specific gene expression. Now we summarize the role of basic region/leucine zipper protein family members and particularly the albumin D site-binding protein (DBP) and the CAAT/enhancer-binding proteins (C/EBPs) for their importance in liver-specific gene expression and their role in liver function and development. Specifically, regulatory networks and molecular interactions were examined in detail, and the experimental findings summarized in this review point to pivotal roles of DBP and C/EBPs in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. These regulatory proteins are therefore of great importance in liver physiology, liver disease, and liver development. Furthermore, interpretation of the vast data generated by novel genomic platform technologies requires a thorough understanding of regulatory networks and particularly the hierarchies that govern transcription and translation of proteins as well as intracellular protein modifications. Thus, this review aims to stimulate discussions on directions of future research and particularly the identification of molecular targets for pharmacological intervention of liver disease.

Address correspondence to: Prof. Dr. Jürgen Borlak, Center for Drug Research and Medical Biotechnology, Fraunhofer Institut für Toxikologie und Experimentelle Medizin, Nicolai Fuchs Str. 1, 30625 Hannover, Germany. E-mail: borlak{at}item.fhg.de




This article has been cited by other articles:


Home page
 Mol. Endocrinol.Home page
N. Wiper-Bergeron, C. St-Louis, and J. M. Lee
CCAAT/Enhancer Binding Protein {beta} Abrogates Retinoic Acid-Induced Osteoblast Differentiation via Repression of Runx2 Transcription
Mol. Endocrinol., September 1, 2007; 21(9): 2124 - 2135.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
J. H Lo, P. P. Chiou, C M Lin, and T. T Chen
Molecular cloning and expression analysis of rainbow trout (Oncorhynchus mykiss) CCAAT/enhancer binding protein genes and their responses to induction by GH in vitro and in vivo
J. Endocrinol., August 1, 2007; 194(2): 393 - 406.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. P. Singh, B. Voleti, and A. Agrawal
A Novel RBP-J{kappa}-Dependent Switch from C/EBPbeta to C/EBP{zeta} at the C/EBP Binding Site on the C-Reactive Protein Promoter
J. Immunol., June 1, 2007; 178(11): 7302 - 7309.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. L. Bennett, B. Hackanson, L. T. Smith, C. D. Morrison, J. C. Lang, D. E. Schuller, F. Weber, C. Eng, and C. Plass
Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein {alpha} Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma
Cancer Res., May 15, 2007; 67(10): 4657 - 4664.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
F. Lehner, U. Kulik, J. Klempnauer, and J. Borlak
The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases
FASEB J, May 1, 2007; 21(7): 1445 - 1462.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
L. Brunelli, K. A. Cieslik, J. L. Alcorn, M. Vatta, and A. Baldini
Peroxisome Proliferator-Activated Receptor-{delta} Upregulates 14-3-3{epsilon} in Human Endothelial Cells via CCAAT/Enhancer Binding Protein-{beta}
Circ. Res., March 16, 2007; 100(5): e59 - e71.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
W. Wei, H. Yang, M. Menconi, P. Cao, C. E. Chamberlain, and P.-O. Hasselgren
Treatment of cultured myotubes with the proteasome inhibitor beta-lactone increases the expression of the transcription factor C/EBPbeta
Am J Physiol Cell Physiol, January 1, 2007; 292(1): C216 - C226.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
N. Venteclef, J. C. Smith, B. Goodwin, and P. Delerive
Liver receptor homolog 1 is a negative regulator of the hepatic acute-phase response.
Mol. Cell. Biol., September 1, 2006; 26(18): 6799 - 6807.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
C. J.F. de Wolf, R. M.J. Cupers, R. M. Bertina, and H. L. Vos
Interleukin-6 Induction of Protein S Is Regulated Through Signal Transducer and Activator of Transcription 3
Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 2168 - 2174.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
J.-B. Beaudry, C. E. Pierreux, G. P. Hayhurst, N. Plumb-Rudewiez, M. C. Weiss, G. G. Rousseau, and F. P. Lemaigre
Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1{alpha} Are Required for Time-Specific Gene Expression during Liver Development.
Mol. Cell. Biol., August 1, 2006; 26(16): 6037 - 6046.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
C. S. Song, I. Echchgadda, Y.-K. Seo, T. Oh, S. Kim, S.-A Kim, S. Cho, L. Shi, and B. Chatterjee
An Essential Role of the CAAT/Enhancer Binding Protein-{alpha} in the Vitamin D-Induced Expression of the Human Steroid/Bile Acid-Sulfotransferase (SULT2A1)
Mol. Endocrinol., April 1, 2006; 20(4): 795 - 808.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
J. Huang, G. Liao, H. Chen, F. Y. Wu, L. Hutt-Fletcher, G. S. Hayward, and S. D. Hayward
Contribution of C/EBP Proteins to Epstein-Barr Virus Lytic Gene Expression and Replication in Epithelial Cells
J. Virol., February 1, 2006; 80(3): 1098 - 1109.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
K. T. Morgan, Z. Jayyosi, M. A. Hower, M. V. Pino, T. M. Connolly, K. Kotlenga, J. Lin, M. Wang, H.-L. Schmidts, M. S. Bonnefoi, et al.
The Hepatic Transcriptome as a Window on Whole-Body Physiology and Pathophysiology
Toxicol Pathol, January 1, 2005; 33(1): 136 - 145.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition
Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics