Cited by 398Genomics and Chromatin DynamicsAcute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processes

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CCAAT Enhancer-Binding Protein (C/EBP) and AML1 (CBFα2) Synergistically Activate the Macrophage Colony-Stimulating Factor Receptor Promoter

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Zhang, Dong-Er, Hetherington, Christopher J., Meyers, Shari, Rhoades, Kristina L., Larson, Christopher J., Chen, Hui-Min, Hiebert, Scott W., Tenen, Daniel G.·1996·Molecular and Cellular Biology

DOI 10.1128/mcb.16.3.1231PMC PMC231105

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Abstract

Transcription factors play a key role in the development and differentiation of specific lineages from multipotential progenitors. Identification of these regulators and determining the mechanism of how they activate their target genes are important for understanding normal development of monocytes and macrophages and the pathogenesis of a common form of adult acute leukemia, in which the differentiation of monocytic cells is blocked. Our previous work has shown that the monocyte-specific expression of the macrophage colony-stimulating factor (M-CSF) receptor is regulated by three transcription factors interacting with critical regions of the M-CSF receptor promoter, including PU.1 and AML1.PU.1 is essential for myeloid cell development, while the AML1 gene is involved in several common leukemia-related chromosome translocations, although its role in hematopoiesis has not been fully identified. Along with AML1, a third factor, Mono A, interacts with a small region of the promoter which can function as a monocyte-specific enhancer when multimerized and linked to a heterologous basal promoter. Here, we demonstrate by electrophoretic mobility shift assays with monocytic nuclear extracts, COS-7 cell-transfected factors, and specific antibodies that the monocyte-enriched factor Mono A is CCAAT enhancer-binding protein (C/EBP). C/EBP has been shown previously to be an important transcription factor involved in hepatocyte and adipocyte differentiation; in hematopoietic cells, C/EBP is specifically expressed in myeloid cells. In vitro binding analysis reveals a physical interaction between C/EBP and AML1. Further transfection studies show that C/EBP and AML1 in concert with the AML1 heterodimer partner CBF beta synergistically activate M-CSF receptor by more then 60 fold. These results demonstrate that C/EBP and AML1 are important factors for regulating a critical hematopoietic growth factor receptor, the M-CSF receptor, suggesting a mechanism of how the AML1 fusion protein could contribute to acute myeloid leukemia. Furthermore, they demonstrate physical and functional interactions between AML1 and C/EBP transcription factor family members.

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Authors: Zhang, D.-E., Hetherington, C. J., Meyers, S., Rhoades, K. L., Larson, C. J., Chen, H.-M., Hiebert, S. W., & Tenen, D. G.
Affiliations: Harvard University (US)
St. Jude Children's Research Hospital (US)
Salk Institute for Biological Studies (US)
Division of Hematology/Oncology, Department of Medicine, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts 02215
ORCID: Zhang, Dong-Er
Larson, Christopher J.
Hiebert, Scott W.
Tenen, Daniel G.
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1996-03-01
Volume: 16
Issue: 3
Pages: 1231-1240
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.16.3.1231
PMC: PMC231105
OpenAlex: W2165787335
Cited by: 396
References: 82
Citations by year: 2026: 3 · 2025: 4 · 2024: 3 · 2023: 10 · 2022: 7 · 2021: 3 · 2020: 2 · 2019: 8 · 2018: 9 · 2017: 14 · 2016: 7 · 2015: 7 · 2014: 10 · 2013: 11 · 2012: 8
FWCI: 10.87
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: McKnight Foundation
St. Jude Children's Research Hospital (CA21765)
American Lebanese Syrian Associated Charities (CA 21765)
National Institutes of Health (CA21765))
National Cancer Institute (CA64140, CA 41456, CA/AI59589, R01CA041456, R01CA064140, P30CA021765)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords: C/EBP, RUNX1, macrophage colony-stimulating factor receptor, transcriptional activation, CBFβ, monocyte differentiation, acute myeloid leukemia, PU.1, hematopoietic transcription factors
MeSH terms: Animals, Base Sequence, Cell Line, DNA-Binding Proteins, Humans, Molecular Sequence Data, Monocytes, Neoplasm Proteins, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Transcription Factors, Signal Transduction, Receptor, Macrophage Colony-Stimulating Factor, CCAAT-Enhancer-Binding Proteins, Core Binding Factor Alpha 2 Subunit

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CCAAT Enhancer-Binding Protein (C/EBP) and AML1 (CBFα2) Synergistically Activate the Macrophage Colony-Stimulating Factor Receptor Promoter

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