Requirement for PLCγ2 in IL-3 and GM-CSF-stimulated MEK/ERK phosphorylation in murine and human hematopoietic stem/progenitor cells

Leon, Carlos Márcio Moura Ponce de; Barbosa, Christiano M.V.; Justo, Giselle Z.; Borelli, Primavera; Resende, José Dias; Oliveira, José Salvador Rodrigues de; Ferreira, Alice Teixeira; Paredes‐Gamero, Edgar Julian

doi:10.1002/jcp.22507

Cited by 28 publications

(39 citation statements)

References 66 publications

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“…We next asked whether the PLC-γ effector Ca 2+ and calmodulin–dependent protein kinase II (CaMKII) was required for efficient ERK phosphorylation in Mx1-Cre, Kras G12D BMMPCs by assessing the inhibitory effects of 2-APB (an IP 3 receptor antagonist) and KN-62 (a CaMKII inhibitor)(36). Like U73122, 2-APB and KN-62 blocked GM-CSF–dependent ERK phosphorylation, whereas BIM I did not (fig.…”

Section: Resultsmentioning

confidence: 99%

PLC-γ and PI3K Link Cytokines to ERK Activation in Hematopoietic Cells with Normal and Oncogenic Kras

et al. 2013

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Oncogenic K-Ras proteins, such as K-RasG12D, accumulate in the active, guanosine triphosphate (GTP)–bound conformation and stimulate signaling through effector kinases. The presence of the K-RasG12D oncoprotein at a similar abundance to that of endogenous wild-type K-Ras results in only minimal phosphorylation and activation of the canonical Raf–mitogen-activated or extracellular signal–regulated protein kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) and phosphoinositide-3 kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) signaling cascades in primary hematopoietic cells, and these pathways remain dependent on growth factors for efficient activation. Here, we show that phospholipase C γ (PLC-γ), PI3K, and their generated second messengers link activated cytokine receptors to Ras and ERK signaling in differentiated bone marrow cells and in a cell population highly enriched for leukemia stem cells. Cells expressing endogenous oncogenic K-RasG12D remained dependent on the second messenger diacylglycerol for the efficient activation of Ras-ERK signaling. These data raise the unexpected possibility of therapeutically targeting proteins that function upstream of oncogenic Ras in cancer.

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Section: Resultsmentioning

confidence: 99%

PLC-γ and PI3K Link Cytokines to ERK Activation in Hematopoietic Cells with Normal and Oncogenic Kras

et al. 2013

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“…Despite the importance of PLCγ2 and ERK1/2 in the hematopoiesis process [26,27], any change in the phosphorylation of these proteins was observed after stimulus with H 2 O 2 . However, a significant alteration was found in the phosphorylation of the protein AKT, which was inhibited in the total HL-60 population (Figure 4C) but not in LSC (Figure 4E).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen peroxide (H2O2) induces leukemic but not normal hematopoietic cell death in a dose-dependent manner

et al. 2013

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Over the last few years, studies have suggested that oxidative stress plays a role in the regulation of hematopoietic cell homeostasis. In particular, the effects of hydrogen peroxide (H2O2) range from hematopoietic cell proliferation to cell death, depending on its concentration in the intracellular milieu. In this work, we evaluated the effects of an oxidative environment on normal and leukemic hematopoietic cells by stimulating normal human (umbilical cord blood) and murine (bone marrow) hematopoietic cells, as well as human myeloid leukemic cells (HL-60 lineage), upon H2O2 stimulus. Total cell populations and primitive subsets were evaluated for each cell type. H2O2 stimulus induces HL-60 cell death, whereas the viability of human and murine normal cells was not affected. The effects of H2O2 stimulus on hematopoietic stem/progenitor cell subsets were examined and the normal primitive cells were found to be unaffected; however, the percentage of leukemic stem cells (LSC) increased in response to H2O2, while clonogenic ability of these cells to generate myeloid clones was inhibited. In addition, H2O2 stimulus caused a decrease in the levels of p-AKT in HL-60 cells, which most likely mediates the observed decrease of viability. In summary, we found that at low concentrations, H2O2 preferentially affects both the LSC subset and total HL-60 cells without damage normal cells.

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“…The involvement of Ca 2+ in cytokine-mediated signaling was recently reported by our group. 33 However, the molecular mechanisms stimulated by Ca 2+ i to carry out the response to ATP and cytokines remain unknown. The Ca 2+ i increase elicited by ATP is large and transiently induced in the cells studied here (Figure 3a).…”

Section: Discussionmentioning

confidence: 99%

Differentiation of hematopoietic stem cell and myeloid populations by ATP is modulated by cytokines

et al. 2011

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Extracellular nucleotides are emerging as important regulators of inflammation, cell proliferation and differentiation in a variety of tissues, including the hematopoietic system. In this study, the role of ATP was investigated during murine hematopoiesis. ATP was able to reduce the percentage of hematopoietic stem cells (HSCs), common myeloid progenitors and granulocyte–macrophage progenitors (GMPs), whereas differentiation into megakaryocyte–erythroid progenitors was not affected. In addition, in vivo administration of ATP to mice reduced the number of GMPs, but increased the number of Gr-1+Mac-1+ myeloid cells. ATP also induced an increased proliferation rate and reduced Notch expression in HSCs and impaired HSC-mediated bone marrow reconstitution in sublethally irradiated mice. Moreover, the effects elicited by ATP were inhibited by suramin, a P2 receptor antagonist, and BAPTA, an intracellular Ca2+ chelator. We further investigated whether the presence of cytokines might modulate the observed ATP-induced differentiation. Treatment of cells with cytokines (stem cell factor, interleukin-3 and granulocyte–monocyte colony stimulator factor) before ATP stimulation led to reduced ATP-dependent differentiation in long-term bone marrow cultures, thereby restoring the ability of HSCs to reconstitute hematopoiesis. Thus, our data suggest that ATP induces the differentiation of murine HSCs into the myeloid lineage and that this effect can be modulated by cytokines.

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Requirement for PLCγ2 in IL-3 and GM-CSF-stimulated MEK/ERK phosphorylation in murine and human hematopoietic stem/progenitor cells

Cited by 28 publications

References 66 publications

PLC-γ and PI3K Link Cytokines to ERK Activation in Hematopoietic Cells with Normal and Oncogenic Kras

PLC-γ and PI3K Link Cytokines to ERK Activation in Hematopoietic Cells with Normal and Oncogenic Kras

Hydrogen peroxide (H2O2) induces leukemic but not normal hematopoietic cell death in a dose-dependent manner

Differentiation of hematopoietic stem cell and myeloid populations by ATP is modulated by cytokines

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