Erythropoietin-dependent autocrine secretion of tumor necrosis factor-alpha in hematopoietic cells modulates proliferation via MAP kinase–ERK-1/2 and does not require tyrosine docking sites in the EPO receptor

Chen, Jingchun; Jacobs-Helber, Sarah M.; Barber, Dwayne L.; Sawyer, Stephen T.

doi:10.1016/j.yexcr.2004.04.009

Cited by 13 publications

(13 citation statements)

References 56 publications

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“…Activation of TNF-R1 suppressed proliferation of hematopoietic stem cells (Rusten et al, 1994;Bryder et al, 2001;Dybedal et al, 2001), and TNF-␣ inhibited proliferation of TNF-R1- expressing neural progenitors in neurospheres derived from neonatal rat striatum (Ben-Hur et al, 2003). Although the effect of TNF-R2 on hippocampal progenitor proliferation observed here was minor and only provided very weak evidence of a stimulatory role, TNF-␣ acting through TNF-R2 has in other studies been reported to promote proliferation of oligodendrocyte progenitors (Arnett et al, 2001) and erythroid cell lines (Chen et al, 2004) and to regulate thymocyte production by stimulating proliferation of early T lymphocyte precursors (Baseta and Stutman, 2000). However, in neither of these other systems was a physiological role of TNF-␣ and its receptors demonstrated.…”

Section: Discussionmentioning

confidence: 44%

“…Moreover, the expression of both receptor subtypes on the progenitors themselves raises the possibility that TNF-R1 and TNF-R2 signaling not only regulates neuronal survival but also has other actions in neurogenesis. Interestingly, TNF-␣ has been shown to affect proliferation of hematopoietic stem/progenitor cells Dybedal et al, 2001;Chen et al, 2004), but none of these studies demonstrated a physiological role of TNF-␣ in the regulation of steady-state hematopoiesis. TNF-␣ was also found to suppress cell proliferation in neurospheres from neonatal rat striatum in vitro (Ben-Hur et al, 2003) and to promote proliferation of oligodendrocyte progenitors and remyelination in a mouse model of demyelination (Arnett et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Tumor Necrosis Factor Receptor 1 Is a Negative Regulator of Progenitor Proliferation in Adult Hippocampal Neurogenesis

Iosif

Ekdahl²,

Ahlenius³

et al. 2006

J. Neurosci.

431

297

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Tumor necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine, acting through the TNF-R1 and TNF-R2 receptors. The two receptors have been proposed to mediate distinct TNF-␣ effects in the CNS, TNF-R1 contributing to neuronal damage and TNF-R2 being neuroprotective. Whether TNF-␣ and its receptors play any role for neurogenesis in the adult brain is unclear. Here we used mouse models with loss of TNF-R1 and TNF-R2 function to establish whether signaling through these receptors could influence hippocampal neurogenesis in vivo under basal conditions, as well as after status epilepticus (SE), which is associated with inflammation and elevated TNF-␣ levels. Notably, in the intact brain, the number of new, mature hippocampal neurons was elevated in TNF-R1Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice, whereas no significant changes were detected in TNF-R2 Ϫ/Ϫ mice. Also after SE, the TNF-R1 Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice produced more new neurons. In contrast, the TNF-R2 Ϫ/Ϫ mice showed reduced SE-induced neurogenesis. Cell proliferation in the dentate subgranular zone was elevated in TNF-R1 Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice both under basal conditions and after SE. The TNF-R2 Ϫ/Ϫ mice either showed no change or minor decrease of cell proliferation. TNF-R1 and TNF-R2 receptors were expressed by hippocampal progenitors, as assessed with reverse transcription-PCR on sorted or cultured cells and immunocytochemistry on cultures. Our data reveal differential actions of TNF-R1 and TNF-R2 signaling in adult hippocampal neurogenesis and identify for the first time TNF-R1 as a negative regulator of neural progenitor proliferation in both the intact and pathological brain.

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Section: Discussionmentioning

confidence: 44%

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor Receptor 1 Is a Negative Regulator of Progenitor Proliferation in Adult Hippocampal Neurogenesis

Iosif

Ekdahl²,

Ahlenius³

et al. 2006

J. Neurosci.

431

297

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“…To address the basis for the failure of EPO to interfere with the chemotherapeutic agents, we evaluated the ability of EPO to signal in MCF-7 cells through well-established pathways that are thought to promote proliferation or cytoprotection, specifically the extracellular signal-regulated kinase (ERK), p38 and c-Jun-NH 2 -kinase (JNK) kinases, Akt (also known as protein kinase B), and signal transducers and activators of transcription (STAT) 5 (22,23,25,27,28). Figure 3 indicates that EPO was effective in promoting the phosphorylation (i.e., activation) of p38, JNK, and ERK in MCF-7 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Apoptosis was detected by the TUNEL assay (21) using the In situ Cell Death Detection kit (Roche, Applied Science, Indianapolis, IN). Apoptosis studies were also conducted by flow cytometry analysis of propidium iodide -stained cells using the FACScan flow cytometer (Becton Dickinson, Rutherford, NJ), as previously described (22,23). Cells containing sub -G 0 -G 1 DNA indicative of apoptosis were gated and shown as a percentage of the total cell numbers.…”

Section: Methodsmentioning

confidence: 99%

“…The signaling proteins of interest were detected first by antiphosphospecific antibodies that recognized only the activated form of the signaling molecules. The blot was stripped of bound antibody and reprobed with an antibody that recognized both phosphorylated and nonphosphorylated forms of the signaling molecules as described previously (22).…”

Section: Methodsmentioning

confidence: 99%

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Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs

Gewirtz

Walker

et al. 2006

Clinical Cancer Research

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Purpose: Erythropoietin (EPO) therapy is widely used for the prevention and treatment of anemia resulting from cancer chemotherapy. Native EPO regulates erythropoiesis, at least in part, by protecting erythroid progenitor cells from apoptotic cell death. The recent discovery of the EPO receptor (EPOR) on cancer cells raises the concern that EPO therapy might stimulate tumor growth and/or protect cancer cells from drug-induced apoptosis. Therefore, the capacity of EPO to interfere with the effects of conventional chemotherapeutic drugs on proliferation, apoptosis, and the induction of senescence was investigated in MCF-7 and MDA-MB231breast tumor cells, which express the EPOR as well as in F-MEL erythroleukemia cells. Experimental Design: Breast cancer cells and F-MEL leukemic cells were cultured in the presence or absence of EPO and then exposed to antitumor drugs. Cell proliferation was assessed by a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay 72 hours after drug exposure. Cytotoxicity was monitored by clonogenic survival. Apoptosis was evaluated either by the terminal deoxyribonucleotide transferase^mediated nick-end labeling assay or fluorescence-activated cell sorting analysis, and senescence was monitored by hgalactosidase staining. EPO signaling was assessed by monitoring the phosphorylation/activation of specific signaling proteins. Results: EPO failed to stimulate the proliferation of MCF-7 or MDA-MB231 breast tumor cells or F-MEL leukemic cells. EPO treatment also failed to interfere with the antiproliferative and/or cytotoxic effects of Adriamycin, Taxol, and tamoxifen in breast tumor cells (or of cytarabine and daunorubicin in F-MEL cells). EPO failed to prevent apoptosis induced by Taxol or senescence induced by Adriamycin in MCF-7 cells. EPO stimulated the activation of extracellular signalregulated kinase, p38, and c-Jun-NH 2 -kinase in MCF-7 cells but did not activate Akt or signal transducers and activators of transcription 5 (STAT5). EPO failed to activate any of these signaling pathways in MDA-MB231cells. Cytarabine and daunorubicin interfered with EPO signaling in F-MEL cells. Conclusions:These findings suggest that EPO is unlikely to directly counteract the effectiveness of cancer chemotherapeutic drugs. This may be a consequence of either ineffective signaling through the EPOR or drug-mediated suppression of EPO signaling.Cancer chemotherapy is often accompanied by severe and debilitating anemia due to both inhibition of erythroid cell maturation in the bone marrow and interference with the ability of the kidney to produce erythropoietin (EPO), the hormone that regulates red blood cell development. Chemotherapy-associated anemia is treated either with EPO in its native form (epoetin-a or epoetin-h, Epogen or Procrit) or a genetically modified form of the drug (Darbepoetin, Aranesp) or transfusion.Because of the potential of EPO to stimulate proliferation of hematopoietic and/or leukemic cells (which may express receptors for EPO and resp...

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Engineering the hematopoietic stem cell niche: Frontiers in biomaterial science

Choi

Mahadik

Harley

2015

Biotechnology Journal

106

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Hematopoietic stem cells (HSCs) play a crucial role in the generation of the body’s blood and immune cells. This process takes place primarily in the bone marrow in specialized ‘niche’ microenvironments, which provide signals responsible for maintaining a balance between HSC quiescence, self-renewal, and lineage specification required for life-long hematopoiesis. While our understanding of these signaling mechanisms continues to improve, our ability to engineer them in vitro for the expansion of clinically relevant HSC populations is still lacking. In this review, we focus on development of biomaterials-based culture platforms for in vitro study of interactions between HSCs and their local microenvironment. The tools and techniques used for both examining HSC-niche interactions as well as applying these findings towards controlled HSC expansion or directed differentiation in 2D and 3D platforms are discussed. These novel techniques hold the potential to push the existing boundaries of HSC cultures towards high-throughput, real-time, and single-cell level biomimetic approaches that enable a more nuanced understanding of HSC regulation and function. Their application in conjunction with innovative biomaterial platforms can pave the way for engineering artificial bone marrow niches for clinical applications as well as elucidating the pathology of blood-related cancers and disorders.

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Erythropoietin-dependent autocrine secretion of tumor necrosis factor-alpha in hematopoietic cells modulates proliferation via MAP kinase–ERK-1/2 and does not require tyrosine docking sites in the EPO receptor

Cited by 13 publications

References 56 publications

Tumor Necrosis Factor Receptor 1 Is a Negative Regulator of Progenitor Proliferation in Adult Hippocampal Neurogenesis

Tumor Necrosis Factor Receptor 1 Is a Negative Regulator of Progenitor Proliferation in Adult Hippocampal Neurogenesis

Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs

Engineering the hematopoietic stem cell niche: Frontiers in biomaterial science

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