Cebpb 12608

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Gene ID: 12608
Gene symbol: cebpb
Gene Description: ccaat/enhancer binding protein (c/ebp), beta
Aliases: CRP2; IL-6DBP; LAP; NF-IL6; NF-M; Nfil6
Human Ortholog Gene ID: [1051]
Reviewer Judgement: TF Gene
Functional Classification: Transcription Factor Binding: tf co-factor binding;

DNA-Binding: sequence-specific

DBD Protein Group Classification: Zipper-Type Group
DBD Protein Group/Family Classification: Zipper-Type Group / Leucine Zipper Family
Homolog Cluster(s): 107503

Evidence:

Pubmed ID Function Species Evidence Strength Reviewer's Comments Reviewer
[15308669] Co-activation; DNA Binding; Transactivation; TF PPI Rat Strong Initial transfections with different C/EBP ({alpha}, {beta}, {gamma}, and {delta}) members clearly showed that only the C/EBP{beta} expression plasmid can act as a repressor for the DSPP promoter (data not shown). We then defined the inhibitory role of C/EBP{beta} on the transcriptional activity of the DSPP gene using a luciferase assay. CMV-driven C/EBP{beta} expression plasmid was transfected with a luciferase reporter in odontoblasts. An increase in concentration of C/EBP{beta} DNA results in a corresponding decrease in the DSPP promoter activity. Individually, C/EBPb and Nrf1 repress DSPP promoter activity to ~50% of initial levels. Synergistically, they reduce activity to 10% as measured by luciferase assay.

To test whether Nrf1 and C/EBP{beta} mutually interact with each other in vivo, cell extracts were prepared from odontoblasts, and the immunoprecipitation assay was carried out with a monoclonal C/EBP{beta} antibody. The presence of Nrf1 in immunoprecipitates was detected by Western blot analysis using a polyclonal antibody against Nrf1.

The direct interaction of Nrf1 and C/EBP{beta} to their putative binding sites on the DSPP promoter was analyzed by EMSA. Protein components from nuclear extracts of odontoblasts formed a clear complex with oligonucleotides containing Nrf1 and C/EBP{beta} binding sequences. The binding of Nrf1 and C/EBP{beta} was confirmed by antibody-mediated supershift. Further, with Nrf1 and C/EBP{beta} antibodies together, a slower migration of the total complex in the gel was observed. EMSA results from the mutated oligonucleotides showed that mutation at the Nrf1 binding site did not affect the binding of C/EBP{beta}, and mutation at the C/EBP{beta} binding site had no effect on the binding of Nrf1 to the DSPP promoter.

To map the Nrf1 and C/EBP{beta} domain that is required for mutual interaction, we performed immunoprecipitation experiments using deletion constructs in pCMV-3XFLAG vectors. Deletions were made at the leucine zipper region of Nrf1 (685�717 amino acids) and C/EBP{beta} (264�285 amino acids). Immunoprecipitation with FLAG antibody followed by cross-blotting with C/EBP{beta} or Nrf1 antibody showed that deletion of the leucine zipper region of either Nrf1 or C/EBP{beta} affected their physical interaction with each other. Deletion of Nrf1 showed that the 480�580 region of the protein was necessary for its inhibitory activity and did not influence binding with C/EBP{beta}. Thus, Nrf1 and C/EBP{beta} mutually interact with each other through their leucine zipper domain.

Shannan HoSui
[15713650] Co-activation; DNA Binding; Transactivation Mouse Medium Cebpb was shown to bind a consensus C/EBP binding element in the osteocalcin gene promoter (C3H10T1/2 cells) using a biotinylated oligonucleotide probe. The deletion of the element suppressed C/EBP�-induced osteocalcin gene promoter activity, whereas the deletion did not affect Runx2-induced promoter activity, as shown by luciferase assay. These data indicate that C/EBP� regulates the osteocalcin gene promoter through association with its DNA binding element. Furthermore, a coimmunoprecipitation experiment confirmed that C/EBP� physically associates with Runx2. Together with the cooperative effects of C/EBP� and Runx2 on ALP activity, these results indicate that C/EBP� controls osteoblast differentiation of mesenchymal cells through a physical association with Runx2.

A naturally occurring isoform of C/EBP�, LIP, exhibits a dominant-negative effect on adipogenesis due to a lack of the transcriptional activation domain. Overexpression of LIP inhibits C/EBP�-induced adipocytic differentiation in C3H10T1/2 cells. LIP overexpression also inhibits the PPAR{gamma} gene promoter activity transactivated by C/EBP� and C/EBP{delta} (luciferase assay).

Shannan HoSui
Additional Reviewer Comments:
Reviewer: Shannan HoSui

C/EBPs are a group of basic leucine zipper transcription factors identified by their sequence-specific binding to the CCAAT motifs in DNA. There are six different C/EBP family members that have been cloned and characterized. All members share homology at the bZIP domain and are multifunctional proteins that exhibit a diverse set of cellular responses like differentiation, inflammatory response, liver regeneration, metabolism etc. The target genes of the C/EBP family members are diverse and various studies have shown that C/EBP can modulate the expression of various matrix genes critical for osteoblast differentiation such as pro-{alpha}1 and -{alpha}2 type I collagen, matrix Gla protein, and osteocalcin. In most cases C/EBP{beta} can form a homodimer and bind to its recognition sequence; however C/EBP{beta} can also intraheterodimerize with other members of the family as well as with a variety of bZIP proteins such as CREB, C/ATF, and AP1. C/EBP{beta} has two major isoforms, liver-enriched activator protein (LAP), which is normally reported to be an activator and liver-enriched inhibitory protein (LIP), which lacks most of the trans -activation domain of LAP and thus acts as a dominant-negative inhibitor. Thus, C/EBP{beta} can directly activate or inhibit target gene expression.


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Facts about Cebpb 12608RDF feed
Gene description ccaat/enhancer binding protein (c/ebp), beta  +
Gene id 12,608  +
Gene judgment TF Gene  +
Gene symbol cebpb  +, CRP2  +, IL-6DBP  +, LAP  +, NF-IL6  +, NF-M  +, and Nfil6  +
Gene taxonomy Transcription Factor Binding: tf co-factor binding  +, and DNA-Binding: sequence-specific  +
Homolog cluster 107,503  +
Protein family 3 Zipper-Type Group/21 Leucine Zipper Family  +
Protein group 3 Zipper-Type Group   +
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