Lacorazza, H. D. et al. The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. Cancer Cell 9, 175-187

Division of Molecular Pharmacology & Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Cancer Cell (Impact Factor: 23.52). 04/2006; 9(3):175-87. DOI: 10.1016/j.ccr.2006.02.017
Source: PubMed


The transcriptional circuitry that regulates the quiescence of hematopoietic stem cells is largely unknown. We report that the transcription factor known as MEF (or ELF4), which is targeted by the t(X;21)(q26;q22) in acute myelogenous leukemia, regulates the proliferation of primitive hematopoietic progenitor cells at steady state, controlling their quiescence. Mef null HSCs display increased residence in G0 with reduced 5-bromodeoxyuridine incorporation in vivo and impaired cytokine-driven proliferation in vitro. Due to their increased HSC quiescence, Mef null mice are relatively resistant to the myelosuppressive effects of chemotherapy and radiation. Thus, MEF plays an important role in the decision of stem/primitive progenitor cells to divide or remain quiescent by regulating their entry to the cell cycle.

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Available from: Yan Liu, Aug 11, 2014
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    • "The quiescent state preserves the stemness of HSCs as well as their ability to efficiently reconstitute ablated hosts upon transplantation. An emerging paradigm suggests that quiescence is controlled by cell intrinsic factors (i.e., Bmi1, Mel18, Mll, ELF4, and c-myb) in addition to microenvironmental cues [1], [2], [3]. Despite its critical role in hematopoiesis, the molecular regulation of quiescence remains a poorly understood process, particularly at the post-transcriptional level [4], [5]. "
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    ABSTRACT: Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G(0)/G(1) switch gene 2 (G0S2) are enriched in lineage(-) Sca-1(+) c-kit(+) (LSK) CD150(+) CD48(-) CD41(-) cells, a population highly enriched for quiescent HSCs, whereas G0S2 expression is suppressed in dividing LSK CD150(+) CD48(-) cells. Gain-of-function analyses using retroviral expression vectors in bone marrow cells showed that G0S2 localizes to the mitochondria, endoplasmic reticulum, and early endosomes in hematopoietic cells. Co-transplantation of bone marrow cells transduced with the control or G0S2 retrovirus led to increased chimerism of G0S2-overexpressing cells in femurs, although their contribution to the blood was reduced. This finding was correlated with increased quiescence in G0S2-overexpressing HSCs (LSK CD150(+) CD48(-)) and progenitor cells (LS(-)K). Conversely, silencing of endogenous G0S2 expression in bone marrow cells increased blood chimerism upon transplantation and promoted HSC cell division, supporting an inhibitory role for G0S2 in HSC proliferation. A proteomic study revealed that the hydrophobic domain of G0S2 interacts with a domain of nucleolin that is rich in arginine-glycine-glycine repeats, which results in the retention of nucleolin in the cytosol. We showed that this cytosolic retention of nucleolin occurs in resting, but not proliferating, wild-type LSK CD150(+) CD48(-) cells. Collectively, we propose a novel model of HSC quiescence in which elevated G0S2 expression can sequester nucleolin in the cytosol, precluding its pro-proliferation functions in the nucleolus.
    PLoS ONE 05/2012; 7(5):e38280. DOI:10.1371/journal.pone.0038280 · 3.23 Impact Factor
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    • "MEF/ELF4 generally promotes cell growth and functions as an oncogene: MEF/ELF4 can transform NIH3T3 cells and is overexpressed in some human ovarian cancer tumor samples (Yao et al., 2007). We generated MEF/ELF4-null mice and subsequently identified its role in regulating both HSC quiescence and self-renewal (Lacorazza et al., 2006). After discovering that MEF/ELF4 can directly regulate MDM2 expression (Sashida et al., 2009), we showed that MEF/ELF4- null long-term reconstituting HSCs (LT-HSCs) and HSCenriched lineage À Sca-1 þ c-kit þ (LSK) cells express high levels of p53 (Liu et al., 2009), that could play an important role in HSC physiology. "
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    ABSTRACT: The p53 tumor suppressor protein is a key transcription factor that regulates several signaling pathways involved in the cell's response to stress. Through stress-induced activation, p53 accumulates and triggers the expression of target genes that protect the genetic integrity of all cells including hematopoietic stem cells (HSCs). These protective mechanisms include cell-cycle arrest, DNA repair, induction of apoptosis, or initiation of senescence. In addition to its function under stress conditions, p53 has important functions during steady-state hematopoiesis, regulating HSC quiescence and self-renewal. In addition, it appears that p53 levels affect HSC competition for the hematopoietic niche, with the less p53 activated HSCs preferentially surviving. The specific genes and precise mechanisms underlying p53's effects on normal HSCs are slowly being clarified. p53 also plays an important role in leukemia stem cell (LSC) behavior, with p53 loss affecting drug resistance and disease progression. Pharmacologic activation of p53 function could overcome the adverse impact of p53 inactivation in LSCs. Thus, understanding the p53 regulatory mechanisms active in HSCs and LSCs may promote the development of new therapeutic strategies that could eliminate the population of largely quiescent LSCs.
    Journal of Cellular Physiology 09/2011; 226(9):2215-21. DOI:10.1002/jcp.22561 · 3.84 Impact Factor
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    • "Besides its function as an activator of cytokines and innate immune molecules, MEF also impacts on cell-cycle progression by promoting the transition of cells from G1 to S phase (7). The loss of MEF was shown to increase tumor suppressor p53 protein and enhance hematopoietic stem cell (HSC) quiescence in murine embryonic fibroblasts, implicating MEF in driving HSC from quiescence to G1 phase by opposing p53 function (14,15). A study previously demonstrated that MEF upregulates the transcription of MDM2, the E3 ubiquitin ligase of p53, thereby suppressing p53 protein stability that led to the inhibition of p53-dependent oncogene-induced cellular senescence (16). "
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    ABSTRACT: Myeloid elf-1-like factor (MEF) or Elf4 is an E-twenty-six (ETS)-related transcription factor with strong transcriptional activity that influences cellular senescence by affecting tumor suppressor p53. MEF downregulates p53 expression and inhibits p53-mediated cellular senescence by transcriptionally activating MDM2. However, whether p53 reciprocally opposes MEF remains unexplored. Here, we show that MEF is modulated by p53 in human cells and mice tissues. MEF expression and promoter activity were suppressed by p53. While we found that MEF promoter does not contain p53 response elements, intriguingly, it contains E2F consensus sites. Subsequently, we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. Nevertheless, E2F1 DNA binding and transactivation of MEF promoter was inhibited by p53 through the association between p53 and E2F1. Furthermore, we showed that activation of p53 in doxorubicin-induced senescent cells increased E2F1 and p53 interaction, diminished E2F1 recruitment to MEF promoter and reduced MEF expression. These observations suggest that p53 downregulates MEF by associating with and inhibiting the binding activity of E2F1, a novel transcriptional activator of MEF. Together with previous findings, our present results indicate that a negative regulatory mechanism exists between p53 and MEF.
    Nucleic Acids Research 01/2011; 39(1):76-88. DOI:10.1093/nar/gkq762 · 9.11 Impact Factor
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