scholarly journals Structural Basis for DNA Recognition by the Basic Region Leucine Zipper Transcription Factor CCAAT/Enhancer-binding Protein α

2003 ◽  
Vol 278 (17) ◽  
pp. 15178-15184 ◽  
Author(s):  
Maria Miller ◽  
Jon D. Shuman ◽  
Thomas Sebastian ◽  
Zbigniew Dauter ◽  
Peter F. Johnson
Keyword(s):  
Transcription Factor ◽  
Leucine Zipper ◽  
Binding Protein ◽  
Dna Recognition ◽  
Structural Basis ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Basic Region

Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein α in myelodysplastic syndromes and acute myeloid leukemias

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1332-1340 ◽  
Author(s):  
Adrian F. Gombart ◽  
Wolf-K. Hofmann ◽  
Seiji Kawano ◽  
Seisho Takeuchi ◽  
Utz Krug ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Leucine Zipper ◽  
Binding Protein ◽  
Nonsmall Cell Lung Cancer ◽  
Dominant Negative ◽  
Myelogenous Leukemia ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Nonsense Codons ◽  
Basic Region

The CCAAT/enhancer binding protein α (C/EBPα) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBPα function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBPα gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelogenous leukemia (AML) subtype M4. The 9 remaining mutations were detected in 1 of 92 (1.1%) myelodysplastic syndrome (MDS) samples and 6 of 78 (7.7%) AML (AML-M2 and AML-M4) samples. Some mutations truncated the predicted protein with loss of the DNA-binding (basic region) and dimerization (leucine zipper [ZIP]) domains by either deletions or nonsense codons. Also, inframe deletions or insertions in the fork region located between the leucine zipper and basic region, or within the leucine zipper, disrupted the α-helical phase of the bZIP domain. The inframe deletion and insertion mutations abrogated the transcriptional activation function of C/EBPα on the granulocyte colony-stimulating factor receptor promoter. These mutants localized properly to the nucleus, but were unable to bind to the C/EBP site in the promoter and did not possess dominant-negative activity. The mutations in the MDS patient and one AML-M2 patient were biallelic, indicating a loss of C/EBPα function. These results suggest that mutation of C/EBPα is involved in specific subtypes of AML and in MDS, but may occur rarely in other types of leukemias or nonhematologic malignancies.

DDRE-30. CELL-PENETRATING PEPTIDE ANTAGONIST OF CCAAT/ENHANCER BINDING PROTEIN ß DISPLAYS POTENT ANTI-GLIOBLASTOMA ACTIVITY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi80-vi81
Author(s):  
Jim Rotolo ◽  
Lila Ghamsari ◽  
Ricardo Ramierez ◽  
Mark Koester ◽  
Siok Leong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Leucine Zipper ◽  
Binding Protein ◽  
Xenograft Model ◽  
Mesenchymal Transition ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Subcutaneous Xenograft ◽  
Peptide Antagonist ◽  
Anti Tumor Activity

Abstract CCAAT/Enhancer Binding Protein Beta (C/EBPß) is a transcription factor overexpressed in glioblastoma (GBM). Mechanistically, C/EBPß is a master regulator of mesenchymal transition in GBM, and its increased expression correlates with mesenchymal differentiation and predicts poor clinical outcome. C/EBPß activity requires dimerization with co-factors such as CREB/ATF family members via leucine zipper interactions. ST101 is a novel peptide antagonist of C/EBPß currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 binds to the C/EBPß leucine zipper, thereby preventing dimer formation and inhibiting its transcriptional activity, resulting in selective tumor cell cytotoxicity. Here, we describe ST101 non-clinical anti-tumor activity against GBM. In vitro studies in T98G and U251 cells demonstrate ST101 dose-dependent impact of cell viability (EC50 of 2.2 and 1.2 μM, respectively), accompanied by significant impact on C/EBPß-mediated gene expression as determined by qPCR analysis. In contrast, normal human mononuclear and epithelial cells were not sensitive to ST101 (EC50 > 80 μM). In vivo, ST101 displayed significant anti-tumor activity in a U251 GBM subcutaneous xenograft model, resulting in 81.4% tumor growth inhibition (TGI) vs. control and undetectable tumors in 50% of animals. Following ST101 exposure tumors displayed reduced BIRC3 and ID2 gene expression, and significantly increased cleaved caspase 3 immunostaining indicative of cell death induction. In U251 tumors, subtherapeutic ST101 (< 5% TGI) in combination with temozolomide (< 5% TGI) resulted in 52.8% TGI, significantly greater than either single-agent alone. Similarly, in a temozolomide-refractory T98G GBM subcutaneous xenograft model, ST101 (41.6% TGI) in combination with TMZ (< 5% TGI) resulted in significant anti-GBM response (72.4% TGI). These data emphasize the potential of ST101 as a potent peptide therapeutic for GBM.

Role of transcription factor CCAAT/enhancer-binding protein alpha in human fetal liver cell typesin vitro

2014 ◽  
Vol 45 (8) ◽  
pp. 919-932 ◽  
Author(s):  
Jörg C. Gerlach ◽  
Patrick Over ◽  
Hubert G. Foka ◽  
Morris E. Turner ◽  
Robert L. Thompson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Liver Cell ◽  
Fetal Liver ◽  
Binding Protein ◽  
Human Fetal Liver ◽  
Fetal Liver Cell ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

scholarly journals A CCAAT/Enhancer Binding Protein β Isoform, Liver-Enriched Inhibitory Protein, Regulates Commitment of Osteoblasts and Adipocytes

2005 ◽  
Vol 25 (5) ◽  
pp. 1971-1979 ◽  
Author(s):  
Kenji Hata ◽  
Riko Nishimura ◽  
Mio Ueda ◽  
Fumiyo Ikeda ◽  
Takuma Matsubara ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Osteoblast Differentiation ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Mesenchymal Cells ◽  
Dominant Negative ◽  
Inhibitory Protein ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

ABSTRACT Although both osteoblasts and adipocytes have a common origin, i.e., mesenchymal cells, the molecular mechanisms that define the direction of two different lineages are presently unknown. In this study, we investigated the role of a transcription factor, CCAAT/enhancer binding protein β (C/EBPβ), and its isoform in the regulation of balance between osteoblast and adipocyte differentiation. We found that C/EBPβ, which is induced along with osteoblast differentiation, promotes the differentiation of mesenchymal cells into an osteoblast lineage in cooperation with Runx2, an essential transcription factor for osteogenesis. Surprisingly, an isoform of C/EBPβ, liver-enriched inhibitory protein (LIP), which lacks the transcriptional activation domain, stimulates transcriptional activity and the osteogenic action of Runx2, although LIP inhibits adipogenesis in a dominant-negative fashion. Furthermore, LIP physically associates with Runx2 and binds to the C/EBP binding element present in the osteocalcin gene promoter. These data indicate that LIP functions as a coactivator for Runx2 and preferentially promotes the osteoblast differentiation of mesenchymal cells. Thus, identification of a novel role of the C/EBPβ isoform provides insight into the molecular basis of the regulation of osteoblast and adipocyte commitment.

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