OM (oncostatin M) activates the human LDLR [LDL (low-density lipoprotein) receptor] gene transcription in HepG2 cells through the SIRE (sterol-independent regulatory element) of LDLR promoter. The SIRE sequence consists of a C/EBP (CCAAT/enhancer-binding protein)-binding site and a CRE (cAMP-response element). Our previous studies [Zhang, Ahlborn, Li, Kraemer and Liu (2002) J. Lipid Res. 43, 1477–1485; Zhang, Lin, Abidi, Thiel and Liu (2003) J. Biol. Chem. 278, 44246–44254] have demonstrated that OM transiently induces EGR-1 (early growth response gene product 1) expression and EGR-1 activates LDLR transcription primarily through a protein–protein interaction with C/EBPβ, which serves as a co-activator of EGR-1. In the present study, we examined the direct role of C/EBPβ as a transactivator in OM-regulated LDLR gene transcription independent of EGR-1. We show that OM induces C/EBPβ expression with kinetics slower than EGR-1 induction. A significant increase in C/EBPβ protein level is detected by 2 h of OM treatment and remains elevated for 24 h. Chromatin immunoprecipitation assays demonstrate that the amount of C/EBPβ bound to the LDLR SIRE sequence is increased 2.8-fold of control by 2 h of OM treatment, reached the highest level of 8-fold by 4 h, and slowly declined thereafter. To further examine the requirement of C/EBPβ in OM-stimulated LDLR expression, we developed a His-tagged dominant-negative mutant of C/EBPβ (His–C/EBPβ-P4; where P4 is plasmid 4 in our mutation series), consisting of the DNA-binding and leucine zipper domains of C/EBPβ (amino acids 246–345). Expression of His–C/EBPβ-P4 in HepG2 cells significantly diminishes the OM-induced increase in LDLR promoter activity and the elevation of endogenous LDLR mRNA expression. Taken together, these new findings identify C/EBPβ as an OM-induced transactivator in LDLR gene transcription and provide a better understanding of the molecular mechanism underlying the sterol-independent regulation of LDLR expression.
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Research Article|
June 14 2006
Blockage of oncostatin M-induced LDL receptor gene transcription by a dominant-negative mutant of C/EBPβ
Yue Zhou;
Yue Zhou
1
*Department of Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, U.S.A.
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Fang Zhang;
Fang Zhang
1
*Department of Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, U.S.A.
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Parveen Abidi;
Parveen Abidi
1
*Department of Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, U.S.A.
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Meihong Lin;
Meihong Lin
*Department of Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, U.S.A.
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Gerald Thiel;
Gerald Thiel
†University of Saarland Medical Center, Homburg, Germany
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Jingwen Liu
Jingwen Liu
2
*Department of Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, U.S.A.
2To whom correspondence should be addressed (email Jingwen.Liu@med.va.gov).
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Publisher: Portland Press Ltd
Received:
January 05 2006
Revision Received:
March 09 2006
Accepted:
March 24 2006
Accepted Manuscript online:
March 24 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 397 (1): 101–108.
Article history
Received:
January 05 2006
Revision Received:
March 09 2006
Accepted:
March 24 2006
Accepted Manuscript online:
March 24 2006
Citation
Yue Zhou, Fang Zhang, Parveen Abidi, Meihong Lin, Gerald Thiel, Jingwen Liu; Blockage of oncostatin M-induced LDL receptor gene transcription by a dominant-negative mutant of C/EBPβ. Biochem J 1 July 2006; 397 (1): 101–108. doi: https://doi.org/10.1042/BJ20060044
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