PU.1 promotes cell cycle exit in the murine myeloid lineage associated with downregulation of E2F1

Ziliotto, Rachel G.; Gruca, Marek R.; Podder, Shreya; Noël, G.; Ogle, Cora K.; Hess, David A.; DeKoter, Rodney P.

doi:10.1016/j.exphem.2013.11.011

Cited by 17 publications

(23 citation statements)

References 48 publications

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“…Spi1 BN/BN cells (BN cells) are fetal liver-derived myeloid progenitor-like cells that proliferate in response to granulocyte-macrophage colonystimulating factor (GM-CSF) (12,13). BN cells express PU.1 at 20% of normal levels, below a threshold required to induce cell cycle arrest and myeloid differentiation, permitting the cells to proliferate indefinitely (13).…”

Section: Resultsmentioning

confidence: 99%

“…Minimal reductions in PU.1 levels are sufficient to induce a preleukemic state with increased proliferation of myeloid progenitors, leading to AML (11). Spi1 BN/BN mice (also called BN mice) express PU.1 at ϳ20% of normal levels, do not generate mature macrophages, and have increased proliferation of myeloid progenitors in the spleen (6,12). Myeloid progenitor cells from Spi1 BN/BN fetal liver (BN cells) proliferate indefinitely in culture in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) without undergoing differentiation (13).…”

mentioning

confidence: 99%

“…Myeloid progenitor cells from Spi1 BN/BN fetal liver (BN cells) proliferate indefinitely in culture in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) without undergoing differentiation (13). Induction of PU.1 in BN cells causes reduced cell cycle progression and myeloid differentiation (12). Therefore, PU.1 is a transcription factor that is essential for the coordination of myeloid terminal differentiation with cell cycle arrest.…”

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confidence: 99%

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Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism

Solomon

Podder

et al. 2017

Molecular and Cellular Biology

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During macrophage development, myeloid progenitor cells undergo terminal differentiation coordinated with reduced cell cycle progression. Differentiation of macrophages from myeloid progenitors is accompanied by increased expression of the E26 transformation-specific transcription factor PU.1. Reduced PU.1 expression leads to increased proliferation and impaired differentiation of myeloid progenitor cells. It is not understood how PU.1 coordinates macrophage differentiation with reduced cell cycle progression. In this study, we utilized cultured PU.1-inducible myeloid cells to perform genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis coupled with gene expression analysis to determine targets of PU.1 that may be involved in regulating cell cycle progression. We found that genes encoding cell cycle regulators and enzymes involved in lipid anabolism were directly and inducibly bound by PU.1 although their steady-state mRNA transcript levels were reduced. Inhibition of lipid anabolism was sufficient to reduce cell cycle progression in these cells. Induction of PU.1 reduced expression of E2f1, an important activator of genes involved in cell cycle and lipid anabolism, indirectly through microRNA 223. Next-generation sequencing identified microRNAs validated as targeting cell cycle and lipid anabolism for downregulation. These results suggest that PU.1 coordinates cell cycle progression with differentiation through induction of microRNAs targeting cell cycle regulators and lipid anabolism. KEYWORDS E2F1, microRNA, PU.1, cell cycle, differentiation, lipid synthesis, myeloid cells A central problem in biology is understanding how cell division is regulated in response to developmental and environmental cues. During macrophage development, proliferating myeloid progenitor cells undergo terminal differentiation that is coordinated with reduced cell cycle progression (1). However, terminally differentiated macrophages are not necessarily permanently cell cycle arrested, as shown by evidence that epidermal Langerhans cells and brain microglia can reenter the cell cycle to self-renew (2, 3). Thus, cell cycle arrest and terminal differentiation, while normally coincident, can be independently and actively regulated. Much remains to be learned about the mechanisms by which cell-type-specific transcription factors coordinate cell cycle arrest with differentiation.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism

Solomon

Podder

et al. 2017

Molecular and Cellular Biology

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“…To determine the consequences of restoring PU.1 expression in CD19-CreDPB cells, we made use of a doxycycline-inducible system (22). A BM-derived CD19-CreDPB pro-B cell line, 660BM, was generated as described in Fig.…”

Section: Pu1 Induces Btk Expression and Loss Of Proliferation In Culmentioning

confidence: 99%

“…Retroviral vectors encoding Tet3G and inducible 3XFLAGPU.1 were produced as previously described (22). Inducible cell lines were maintained in medium containing 0.5 mg/ml puromycin (BioBasic, Markham, ON, Canada).…”

Section: Cell Culturementioning

confidence: 99%

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Christie

Turkistany

et al. 2015

The Journal of Immunology

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Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro–B cells from CD19-CreΔPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro–B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro–B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells.

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Transcription Factor PU.1

Batista¹,

DeKoter²

2016

Encyclopedia of Signaling Molecules

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PU.1 promotes cell cycle exit in the murine myeloid lineage associated with downregulation of E2F1

Cited by 17 publications

References 48 publications

Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism

Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Transcription Factor PU.1

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