Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells

Kolonics, Attila; Apáti, Ágota; Jánossy, Judit; Brózik, Anna; Gáti, Róbert; Schaefer, András; Magócsi, Mária

doi:10.1016/s0898-6568(01)00201-7

Cited by 48 publications

(41 citation statements)

References 72 publications

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“…Indeed, it has been suggested that the ERK MAPK pathway may not be the principal mechanism of Epo activity (Kolonics et al, 2001). Consequently, the particular involvement of ERK, and its associated adverse effects of reducing drug sensitivity, may in fact be less of an issue in Epo-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of haemopoietic growth factors on cancer cell lines and their role in chemosensitivity

et al. 2003

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The recombinant growth factors (GFs) erythropoietin (Epo) and granulocyte-macrophage colony stimulating factor (GM-CSF) have important roles in the management of cancer patients. However, the effects of these GFs at a cellular level are not well understood. We examined the effect of GFs alone, and in combination with cytotoxic chemotherapy, in a panel of seven cell lines. Flow cytometric analysis showed varying levels of receptor expression, which correlated with phosphorylated MAPK expression. Additionally, there were also concomitant increases in BCL-2 protein levels in those cells with high levels of MAPK activation. Although culturing cells with Epo or GM-CSF did not alter cell viability by themselves, GF pretreatment in cell lines expressing higher receptor levels resulted in a reduced magnitude of cell kill following exposure to cytotoxic IC 50 concentrations of cisplatin. Subsequent co-culture with either the MEK inhibitor U0126 or the GM-CSF antagonist E21R negated this induced resistance to cytotoxic chemotherapy, confirming the importance of the GF receptor as well as MAPK in mediating these effects. These results suggest that the use of GFs during chemotherapy may be detrimental in those cancers expressing higher levels of the specific receptor. Conversely, our results also suggest that GFs are safe to use in chemotherapeutic regimens if the cancer cells do not overexpress the particular receptor.

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Section: Discussionmentioning

confidence: 99%

Effect of haemopoietic growth factors on cancer cell lines and their role in chemosensitivity

et al. 2003

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“…ERK1/2 activation has also been involved in mediating differentiation along the megakaryocytic and myeloid lineages. The ERK1/2 pathway antagonizes erythroid differentiation (39), whereas this pathway is necessary for GM-CSFinduced proliferation (40). Mutational analysis of G-CSF receptor indicates that ERK activation rather than STAT3 activation is required for proliferation (41).…”

Section: Effects Of Spred-1 On Proliferation and Differentiation Of Pmentioning

confidence: 99%

Spred-1 Negatively Regulates Interleukin-3-mediated ERK/Mitogen-activated Protein (MAP) Kinase Activation in Hematopoietic Cells

Nonami

Kato

Taniguchi

et al. 2004

Journal of Biological Chemistry

105

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Sprouty/Spred family proteins have been identified as negative regulators of growth factor-induced ERK/mitogen-activated protein (MAP) kinase activation. However, it has not been clarified whether these proteins regulate cytokine-induced ERK activity. We found that Spred-1 is highly expressed in interleukin-3 (IL-3)-dependent hematopoietic cell lines and bone marrow-derived mast cells. To investigate the roles of Spred-1 in hematopoiesis, we expressed wild-type Spred-1 and a dominant negative form of Spred-1, ⌬C-Spred, in IL-3-and stem cell factor (SCF)-dependent cell lines as well as hematopoietic progenitor cells from mouse bone marrow by retrovirus gene transfer. In IL-3-dependent Ba/F3 cells expressing c-kit, forced expression of Spred-1 resulted in a reduced proliferation rate and ERK activation in response to not only SCF but also IL-3. In contrast, ⌬C-Spred augmented IL-3-induced cell proliferation and ERK activation. Wild-type Spred-1 inhibited colony formation of bone marrow cells in the presence of cytokines, whereas ⌬C-Spred-1 expression enhanced colony formation. Augmentation of ERK activation and proliferation in response to IL-3 was also observed in Spred-1-deficient bone marrow-derived mast cells. These data suggest that Spred-1 negatively regulates hematopoiesis by suppressing not only SCFinduced but also IL-3-induced ERK activation.Receptor tyrosine kinases, such as stem cell factor (SCF) 1 receptor (c-kit), as well as cytokine receptors including interleukin (IL)-3 or erythropoietin (EPO) receptor activate the extracellular signal-regulated kinase (ERK) cascade. ERK activation is initiated by binding of Grb2 to the phosphorylated tyrosine residues of the receptor or phosphorylated adaptor molecules such as Shc, FRS-2, IRS-1/2, SHP-2, and Gab-1. The complex of Grb2 and SOS (son of sevenless) activates Ras by GTP loading. Ras-GTP recruits Raf1 to the plasma membrane (1, 2), which is then phosphorylated and activated by several, not well defined, kinases with complex regulatory mechanisms (3-5). Activated Raf then phosphorylates and activates the dual-specific kinase MEK, which phosphorylates and activates ERKs. In addition, the Ras-independent Raf1-ERK activation mechanism has been recently demonstrated, and members of the protein kinase C family of serine/threonine kinases have been implicated as potential activators of Raf (6).Mitogen-activated protein (MAP) kinases including ERKs play important roles in hematopoiesis. Most hematopoietic cytokines (hematopoietins) activate the JAK-STAT and Ras-ERK pathways, both being required for a satisfactory level of proliferation and differentiation of hematopoietic cells. For example, STAT5 activation is not sufficient for EPO-dependent growth of CTLL2 cells expressing EPO receptor, but additional activation of MAP kinases can support their cellular proliferation in response to EPO (7). MAP kinases have also been shown to play a critical role in megakaryopoiesis by c-mpl (8). However, little is known about how MAP kinase is regulated in hematopoietic cell...

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“…To further establish whether expressed Bcl-2 was functionally active, cells were depleted with GM-CSF. The TF-1 cell line has been reported to undergo apoptosis upon growth factor deprivation (Kolonics et al, 2001), which can be suppressed by overexpression of Bcl-2 (Kitamura et al, 1989;Alvarado-Moreno et al, 2000). Upon GM-CSF withdrawal ( Figure 4B), 30% of the control cell population underwent apoptosis as determined by the number of cells with fragmented DNA (subG1), whereas in bcl-2-transfected cells DNA fragmentation was inhibited completely.…”

Section: Sensitisation To Tnf-induced Apoptosis By Mithramycin Is Casmentioning

confidence: 99%

The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF)

Duverger¹,

Murphy²,

Sheehan³

et al. 2004

Br J Cancer

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In this report we show that mithramycin considerably increases the direct cytotoxic effect of tumour necrosis factor (TNF) on tumour cells in vitro. Sensitisation to TNF-induced apoptosis was prevented by the broad caspase inhibitor zVAD-fmk, whereas overexpression of Bcl-2 had no effect. Mithramycin also potentiated cell death induced by Fas agonistic antibodies. In contrast, mithramycin reduced the percentage of cells undergoing apoptosis due to factor withdrawal. TNF-induced activation of NF-kappaB (NF-kB)-dependent gene expression was not modulated by mithramycin treatment. Concomitantly with the increased sensitivity, the protein level of the short-spliced cFLIP variant was downregulated. These results indicate that mithramycin enhances TNF-induced cell death in an NF-kB-independent manner, and suggest that the Fas-associated death domain protein plays a crucial role in the TNFsensitising effect of mithramycin.

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Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells

Cited by 48 publications

References 72 publications

Effect of haemopoietic growth factors on cancer cell lines and their role in chemosensitivity

Effect of haemopoietic growth factors on cancer cell lines and their role in chemosensitivity

Spred-1 Negatively Regulates Interleukin-3-mediated ERK/Mitogen-activated Protein (MAP) Kinase Activation in Hematopoietic Cells

The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF)

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