The DOI matches its Crossref record; 72 of the 73 references it cites were found in a registry or an index.
PU.1 (Spi-1) and C/EBPα Regulate Expression of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Gene
Open accessAbstract
Growth factor receptors play an important role in hematopoiesis. In order to further understand the mechanisms directing the expression of these key regulators of hematopoiesis, we initiated a study investigating the transcription factors activating the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha gene. Here, we demonstrate that the human GM-CSF receptor alpha promoter directs reporter gene activity in a tissue-specific fashion in myelomonocytic cells, which correlates with its expression pattern as analyzed by reverse transcription PCR. The GM-CSF receptor alpha promoter contains an important functional site between positions -53 and -41 as identified by deletion analysis of reporter constructs. We show that the myeloid and B cell transcription factor PU.1 binds specifically to this site. Furthermore, we demonstrate that a CCAAT site located upstream of the PU.1 site between positions -70 and -54 is involved in positive-negative regulation of the GM-CSF receptor alpha promoter activity. C/EBP alpha is the major CCAAT/enhancer-binding protein (C/EBP) form binding to this site in nuclear extracts of U937 cells. Point mutations of either the PU.1 site or the C/EBP site that abolish the binding of the respective factors result in a significant decrease of GM-CSF receptor alpha promoter activity in myelomonocytic cells only. Furthermore, we demonstrate that in myeloid and B cell extracts, PU.1 forms a novel, specific, more slowly migrating complex (PU-SF) when binding the GM-CSF receptor alpha promoter PU.1 site. This is the first demonstration of a specific interaction with PU.1 on a myeloid PU.1 binding site. The novel complex is distinct from that described previously as binding to B cell enhancer sites and can be formed by addition of PU.1 to extracts from certain nonmyeloid cell types which do not express PU.1, including T cells and epithelial cells, but not from erythroid cells. Furthermore, we demonstrate that the PU-SF complex binds to PU.1 sites found on a number of myeloid promoters, and its formation requires an intact PU.1 site adjacent to a single-stranded region. Expression of PU.1 in nonmyeloid cells can activate the GM-CSF receptor alpha promoter. Deletion of the amino-terminal region of PU.1 results in a failure to form the PU-SF complex and in a concomitant loss of transactivation, suggesting that formation of the PU-SF complex is of functional importance for the activity of the GM-CSF receptor alpha promoter. Finally, we demonstrate that C/EBP alpha can also active the GM-CSF receptor alpha promoter in nonmyeloid cells. These results suggest that PU.1 and C/EBP alpha direct the cell-type-specific expression of GM-CSF receptor alpha, further establish the role of PU.1 as a key regulator of hematopoiesis, and point to C/EBP alpha as an additional important factor in this process.
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In the citing paper
“PU.1 imparts its key functions by regulating vast number of myeloid gene promoters that include GM-CSF receptor a, M-CSF receptor (M-CSFR), scavenger receptor CD163, and CD11b, etc (6,7).”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In cotransfection experiments, RUNX1, PU.1, and CEBPA play essential roles in activation of the hematopoietic differentiation genes MCSFR and GMCSFR.7,8,31”
From RUNX1 regulates corepressor interactions of PU.1 (2011) · cites this paper as [31]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The block in the development of these lineages occurs at very early stages, because the mutant animals completely lack lymphoid and myeloid progenitor cells, rendering it difficult to determine the precise role of PU.1 during stage- and lineage-specific gene expression.”
From AKT Induces Transcriptional Activity of PU.1 through Phosphorylation-mediated Modifications within Its Transactivation Domain (2001) · cites this paper as [67]
Experimental — accuracy not yet measuredIn the citing paper
“In myeloid lineages, the putative PU.1 target genes include G-SCF receptor [23], GM-CSF receptor [24] and M-CSF receptor [25].”
From PU.1 and partners: regulation of haematopoietic stem cell fate in normal and malignant haematopoiesis (2009) · cites this paper as [24]
In the citing paper
“C/EBP-α expression is prominent in immature myeloid cells [24, 101].”
From PU.1 and partners: regulation of haematopoietic stem cell fate in normal and malignant haematopoiesis (2009) · cites this paper as [24]
In the citing paper
“Each factor has been shown to synergize on various promoters, including M-CSF receptor promoter and neutrophil elastase (NE) promoter [24, 63].”
From PU.1 and partners: regulation of haematopoietic stem cell fate in normal and malignant haematopoiesis (2009) · cites this paper as [24]
In the citing paper
“C/EBP-␣ minimally activates several myeloid cell-specific promoters, including those for cytokine receptors (e.g., GM-CSF, G-CSF, and M-CSF receptors) (26,65,78,79) and granule proteins (e.g., NE) (50).”
From The t(8;21) Fusion Product, AML-1–ETO, Associates with C/EBP-α, Inhibits C/EBP-α-Dependent Transcription, and Blocks Granulocytic Differentiation (1998) · cites this paper as [26]
In the citing paper
“Moreover, C/EBP-␣ cooperates with other myeloid transcription factors, including AML-1B and PU.1, to synergistically upregulate the expression of several myeloid cellspecific promoters (26,50,78).”
From The t(8;21) Fusion Product, AML-1–ETO, Associates with C/EBP-α, Inhibits C/EBP-α-Dependent Transcription, and Blocks Granulocytic Differentiation (1998) · cites this paper as [26]
In the citing paper
“Each factor has been shown to synergize on various promoters, including M-CSF receptor promoter and neutrophil elastase promoter.15,35”
From Granulocyte inducer C/EBPα inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions (2002) · cites this paper as [15]
In the citing paper
“Targeted disruption of PU.1 in mice severely impairs the development of lymphoid (B cells) and myeloid (macrophages and neutrophils) lineages.”
From AKT Induces Transcriptional Activity of PU.1 through Phosphorylation-mediated Modifications within Its Transactivation Domain (2001) · cites this paper as [67]
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CCAAT-enhancer binding proteinα is expressed in activated microglial cells after brain injury
Walton, M., Saura, J., Young, D., MacGibbon, G., Hansen, W., Lawlor, P., Sirimanne, E., Gluckman, P., & Dragunow, M. (1998) · Molecular Brain Research · doi:10.1016/s0169-328x(98)00169-7 · Cited by 28
Mikhail, F. M., Coignet, L., Hatem, N., Mourad, Z., Farawela, H. M., Elkaffash, D. M., Farahat, N. M. G., & Nucifora, G. (2003) · Genes Chromosomes and Cancer · doi:10.1002/gcc.10302 · Cited by 28
“GM-CSF, M-CSF receptor, myeloperoxidase, neutrophil elastase, granzyme B, and subunits of the T-cell antigen receptor (Redondo et al., 1992; Suzow et al., 1993; Wang et al., 1993; Nuchprayoon et al., 1994; Zhang et al., 1994; Hohaus et al., 1995; Wargnier et al., 1995; Uchida et al., 1997).”
BackgroundThe transcription factor PU.1 does not regulate lineage commitment but has lineage-specific effects
McKercher, S. R., Henkel, G. W., & Maki, R. A. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.5.727 · Cited by 28
Sonn, I., Honda‐Ozaki, F., Yoshimatsu, S., Morimoto, S., Watanabe, H., & Okano, H. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00201-1 · Cited by 30
“1 is reportedly crucial for the differentiation of both cell types [21, 62].”
BackgroundKatzenback, B. A., Katakura, F., & Belosevic, M. (2015) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2015.10.024 · Cited by 28
Palani, S., & Sarkar, C. A. (2009) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000518 · Cited by 28
Hashimoto, S., Nishizumi, H., Hayashi, R., Tsuboi, A., Nagawa, F., Takemori, T., & Sakano, H. (1999) · International Immunology · doi:10.1093/intimm/11.9.1423 · Cited by 27
Hirouchi, T., Takabatake, T., Yoshida, K., Nitta, Y., Nakamura, M. M., Tanaka, S., Ichinohe, K., Oghiso, Y., & Tanaka, K. J. (2008) · Experimental Hematology · doi:10.1016/j.exphem.2008.01.015 · Cited by 27
Li, X., Vradii, D., Gutiérrez, S., Lian, J. B., van Wijnen, A. J., Stein, J. L., Stein, G. S., & Javed, A. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20548 · Cited by 27
“The human M-CSF receptor c-FMS promoter fragment ( 416 to þ71 bp) fused to the luciferase gene was a kind gift of D.G. Tenen, Harvard Institutes of Medicine [Hohaus et al., 1995].”
BackgroundMethodInfluentialvan Dijk, T. B., Baltus, B., Caldenhoven, E., Handa, H., Raaijmakers, J. A. M., Lammers, J. J., Koenderman, L., & de Groot, R. P. (1998) · Blood · doi:10.1182/blood.v92.10.3636 · Cited by 24
Humbert, M., Federzoni, E. A., Britschgi, A., Schläfli, A. M., Valk, P. J. M., Kaufmann, T., Haferlach, T., Behre, G., Simon, H., Torbett, B. E., et al. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.1112608 · Cited by 26
Modeling the Hematopoietic Landscape
Brown, G., & Ceredig, R. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00104 · Cited by 27
Molecular and Cellular Aspects of Macrophage Aging
Sebastián, C., Lloberas, J., & Celada, A. (2009) · Springer eBooks · doi:10.1007/978-1-4020-9063-9_46 · Cited by 24
Dominant-interfering C/EBPα stimulates primitive erythropoiesis in zebrafish
Liu, T. X., Rhodes, J., Deng, M., Hsu, K., Radomska, H. S., Kanki, J. P., Tenen, D. G., & Look, A. T. (2007) · Experimental Hematology · doi:10.1016/j.exphem.2006.10.008 · Cited by 24
“CEBPA is strongly expressed in granulocyte/monocyte progenitors (GMPs) of human and rodent bone marrow and is specifically upregulated during granulocytic differentiation [1-4].”
BackgroundKoyama, N., Hoelzer, D. F., & Ottmann, O. G. (2004) · European Journal of Immunology · doi:10.1002/eji.200324420 · Cited by 22
The Granulocyte Colony-Stimulating Factor Receptor and Its Role in Disorders of Granulopoiesis
Avalos, B. R. (1998) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428199809092682 · Cited by 22
Taylor, S. J., Stauber, J., Bohorquez, O., Tatsumi, G., Kumari, R., Chakraborty, J., Bartholdy, B. A., Schwenger, E., Sundaravel, S., Farahat, A. A., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01911-7 · Cited by 22
Uchiumi, F., Sakakibara, G., Sato, J., & Tanuma, S.-I. (2008) · Genes to Cells · doi:10.1111/j.1365-2443.2008.01240.x · Cited by 21
“PU.1-binding sequences are found in promoter regions of proteins, including macrophage colony-stimulating factor (M-CSF) receptor (Zhang et al. 1994), and granulocyte-macrophage colonystimulating factor (GM-CSF) receptor α (Hohaus et al. 1995).”
BackgroundHematopoietic Stem Cell Molecular Targets and Factors Essential for Hematopoiesis
Raghav, P. K., & Gangenahalli, G. U. (2018) · Journal of Stem Cell Research & Therapy · doi:10.4172/2157-7633.1000441 · Cited by 22
“1 also interacts synergistically or antagonistically with c-Jun, C/EBPδ, GATA-1, GATA-2, C/EBPα, c-Myb, CBP, AML-1B, AML-1/ETO, NF-EMS/Pip/IRF-4, and ICSBP/IRF-8, which governs most of the genes [37-47].”
BackgroundTranscriptional and epigenetic regulation of the GM-CSF promoter by RUNX1
Taberlay, P. C., James, S. R., Qadi, A. A., West, A. C., Ray, S., Bert, A. G., Cockerill, P. N., & Holloway, A. F. (2010) · Leukemia Research · doi:10.1016/j.leukres.2010.03.029 · Cited by 22
AML1B transcriptional repressor function is impaired by the Flt3‐internal tandem duplication
Takahashi, S., Harigae, H., Kameoka, J., Sasaki, T., & Kaku, M. (2005) · British Journal of Haematology · doi:10.1111/j.1365-2141.2005.05621.x · Cited by 21
“These include the genes encoding IL-3 (Uchida et al, 1997), granulocyte–macrophage colony-stimulating factor (GM-CSF) (Hohaus et al, 1995), CSF 1 receptor (Zhang et al, 1994a), protein kinase C beta (Hug et al, 2004), and p21 (Lutterbach et al, 2000).”
BackgroundTerminal Differentiation of Dendritic Cells
Seillet, C., & Belz, G. T. (2013) · Advances in immunology · doi:10.1016/b978-0-12-417028-5.00007-7 · Cited by 25
Popernack, P. M., Truong, L., Kamphuis, M. M. J., & Henderson, A. J. (2001) · Stem Cells and Development · doi:10.1089/152581601753193841 · Cited by 19
A minimal c-fes cassette directs myeloid-specific expression in transgenic mice
Heydemann, A., Warming, S., Clendenin, C., Sigrist, K. S., Hjorth, J. P., & Simon, M. C. (2000) · Blood · doi:10.1182/blood.v96.9.3040 · Cited by 20
Faust, N., Bonifer, C., & Sippel, A. E. (1999) · DNA and Cell Biology · doi:10.1089/104454999315042 · Cited by 20
“…example, been found in the promoter regions of the genes for macrophage colony-stimulating factor receptor (M-CSFR) or granulocyte colony-stimulating factor receptor (G-CSFR) (Zhang et al. , 1996a; Hohaus et al. , 1995) as well as the 2 6.1 kb chicken lysozyme enhancer (Goethe and Phi Van, 1994).”
InfluentialRooney, J. W., & Calame, K. L. (2001) · Genes & Development · doi:10.1101/gad.937201 · Cited by 20
RetractedC/EBPβ regulates human immunodeficiency virus 1 gene expression through its association with cdk9
Mameli, G., Deshmane, S. L., Ghafouri, M., Cui, J., Simbiri, K. O., Khalili, K., Mukerjee, R., Dolei, A., Amini, S., & Sawaya, B. E. (2007) · Journal of General Virology · doi:10.1099/vir.0.82487-0 · Cited by 19
“…to interact with components of the basal transcriptional machinery such as the TATA-binding protein and transcription factor IIB (Nerlov & Ziff, 1995) and other transcription factors, including Nf-kB and the cAMP response element-binding protein (Hohaus et al., 1995; Westendorf et al., 1998).”
BackgroundMiliti, S., Riccioni, R., Parolini, I., Sposi, N. M., Samoggia, P., Pelosi, E., Testa, U., & Peschle, C. (2000) · British Journal of Haematology · doi:10.1046/j.1365-2141.2000.02348.x · Cited by 19
PU.1 regulates glutathione peroxidase expression in neutrophils
Throm, S. L., & Klemsz, M. J. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0203061 · Cited by 19
Sun, Z., Yergeau, D. A., Wong, I. C., Tuypens, T., Tavernier, J. H., Paul, C. C., Baumann, M. A., Auron, P. E., Tenen, D. G., & Ackerman, S. J. (1996) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-85232-9_18 · Cited by 19
RUNX1-RUNX1 Homodimerization Modulates RUNX1 Activity and Function
Li, D., Sinha, K. K., Abdul‐Hay, M., Rinaldi, C. R., Saunthararajah, Y., & Nucifora, G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700074200 · Cited by 18
Dendritic Cell Development: A Choose-Your-Own-Adventure Story
Moore, A. J., & Anderson, M. K. (2013) · Advances in Hematology · doi:10.1155/2013/949513 · Cited by 18
Transcriptional Regulation of c-fms Gene Expression
Xie, Y., Chen, C., & Hume, D. A. (2001) · Cell Biochemistry and Biophysics · doi:10.1385/cbb:34:1:001 · Cited by 19
Hong, S., Lee, M. Y., & Cheong, J. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.4727 · Cited by 18
PU.1 regulates the expression of the human neutrophil elastase gene
Srikanth, S., & Rado, T. A. (1998) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(98)00039-6 · Cited by 18
Exploring the Interplay between Bone Marrow Stem Cells and Obesity
Moscatelli, F., Monda, A., Messina, G., Picciocchi, E., Monda, M., di Padova, M., Monda, V., Mezzogiorno, A., Dipace, A., Limone, P., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052715 · Cited by 17
Sive, J. I., Basilico, S., Hannah, R., Kinston, S., Calero‐Nieto, F. J., & Göttgens, B. (2015) · Leukemia · doi:10.1038/leu.2015.172 · Cited by 17
Diabetes Inhibits Gr-1+ Myeloid Cell Maturation via Cebpa Deregulation
Wicks, K., Torbica, T., Umehara, T., Amin, S., Bobola, N., & Mace, K. A. (2015) · Diabetes · doi:10.2337/db14-1895 · Cited by 17
“In addition, CEBPA activates CSf2ra, which encodes GM-CSF receptor a (GM-CSFRa) (31) and is downregulated by 0.”
Background
Metadata
- Authors
- Hohaus, S., Petrovick, M. S., Voso, M. T., Sun, Z., Zhang, D.-E., & Tenen, D. G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Tenen, Daniel G.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1995-10-01
- Volume
- 15
- Issue
- 10
- Pages
- 5830-5845
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC230835
- OpenAlex
- W2161743101
- Cited by
- 284
- References
- 73
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 5 · 2013: 7 · 2012: 6
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Funders
- American Lung Association
- National Cancer Institute (CA 41456, R01CA041456)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048660, DK48660)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- PU.1, SPI-1, C/EBPα, GM-CSF receptor alpha, transcription factor binding sites, myelomonocytic cells, B cells, promoter regulation, transcriptional activation, hematopoiesis, single-stranded DNA binding, U937 cells
- MeSH terms
- Amino Acid Sequence, B-Lymphocytes, Base Sequence, Cell Line, DNA, DNA-Binding Proteins, DNA, Single-Stranded, Hematopoiesis, Humans, Methylation, Molecular Sequence Data, Monocytes, Mutation, Nuclear Proteins, Promoter Regions, Genetic, T-Lymphocytes, Transcription Factors, Transcriptional Activation, Retroviridae Proteins, Oncogenic, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Genes, Reporter, CCAAT-Enhancer-Binding Proteins
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