Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines

Miranda, Michelle B.; McGuire, Terence F.; Johnson, Daniel E.

doi:10.1038/sj.leu.2402400

Cited by 145 publications

(122 citation statements)

References 53 publications

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“…27,38 ERK signaling may have an important role in PMA-and ATRA-induced leukemia cell differentiation. [39][40][41] As reported by Lee's group, ERK2 activation is necessary for ATRA-induced differentiation. 39 Here, we also showed that the inhibition of ERK by U0126 could partially antagonize PMA and ATRA-induced differentiation of U937 cells (Supplementary Figure S10).…”

Section: Discussionmentioning

confidence: 97%

The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation

Huang

Hou

et al. 2010

Leukemia

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Onzin is a small, novel, and highly conserved protein with unique structure and tissue-restricted expression. The regulation of its expression and biological roles remain greatly elusive. Here, we provide the first demonstration that onzin expression is significantly downregulated during differentiation induction of acute myeloid leukemic (AML) cell lines and primary cells by all-trans retinoic acid (ATRA) and especially by phorbol 12-myristate 13-acetate (PMA). Applying chemical inhibitions, RNA interferences, and transfected expressions of dominant negative mutants or constitutive catalytic forms of the related kinases, we show that protein kinase C-e (PKCe)-extracellular signal-regulated protein kinase 2 (ERK2) signaling axis is required for PMA-induced downregulation of onzin expression. The ectopic expression of onzin partially inhibits PMA-induced monocytic differentiation of AML cells, whereas suppression of onzin by specific short hairpin RNAs enhances PMA-induced differentiation to a degree. Furthermore, onzin partially inhibits the transcriptional activity of hematopoiesisrelated important transcription factor PU.1 via their interaction. Taken together, our results show that PMA downregulates onzin expression through PKCe-ERK2 signaling pathway, which favors monocytic differentiation of leukemic cells.

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Section: Discussionmentioning

confidence: 97%

The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation

Huang

Hou

et al. 2010

Leukemia

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“…Most studies dealing with activation of the Raf-MEK-ERK pathway, however, show relatively equal activation of both ERK-1 and ERK-2. However, one study focusing on Raf-MEK-ERK has shown dramatically greater phosphorylation of ERK-2, specifically after retinoic acid activation of Raf-MEK-ERK signaling in myeloid cell cultures (Miranda et al, 2002). Another study that actually dealt with the valine-12 Ras mutation showed that ERK-1 was preferentially phosphorylated as a result of the Ras mutation, and the phosphorylation state of ERK-2 was relatively unchanged in human kidney 293T cells (Recio et al 2000).…”

Section: Discussionmentioning

confidence: 99%

RasMutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

Mullin

Leatherman

Valenzano

et al. 2005

MBoC

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Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK 1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of D-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to D-mannitol (M r 182), polyethylene glycol (M r 4000), and 10,000-M r methylated dextran but not to 2,000,000-M r methylated dextran. This implies a "ceiling" on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier. INTRODUCTIONMutations in the three closely related ras genes, H-ras, K-ras, and N-ras, are among the most common mutations found in human cancer, reaching 50% in some types of tumors, such as colorectal carcinoma (Forrester et al., 1987;Andreyev et al., 1997Andreyev et al., , 1998Andreyev et al., , 2001). Vogelstein and colleagues have shown that mutations in K-ras occur early in the development of colon carcinomas (Vogelstein et al., 1988). This dominantly acting mutation in ras results in its constitutive activation and the subsequent triggering of its signaling pathway by influencing GTPase activity. It is clear that mutations in ras contribute both to the recurrence of the disease and to decreased survival (Andreyev et al., 1998). It is less clear, however, what the consequences of ras mutations are during the early stages of tumorigenesis. In this regard, one important issue is the effect of Ras activation on epithelial barrier function, perhaps the most basic of all epithelial functions, and a function shared by all epithelial tissues. Ras can exert fundamental effects on epithelial barrier function through the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase pathway or through direct binding to the tight junction-associated protein, AF-6, which binds to ZO-1, which in turn links the tight junction to the actin cytoskeleton. Activated Ras is known to inhibit interaction between the tight junction-associated proteins, AF-6 and ZO-1, with resultant perturbation of intercellular junctions (Yamamoto et al., 1997). Modulation of tight junctions by G proteins in ge...

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“…MEK1/2 phosphorylation (Ser217/ 221), which is upstream of Erk1/2 and contributes to G-CSFinduced myeloid cell differentiation, 31 was not induced by G-CSF stimulation in bone marrow MNCs from Gfi1 Ϫ/Ϫ mice but was induced in MNCs from Gfi1 ϩ/ϩ controls ( Figure 1F). By contrast, we detected a similar degree of basal Src activity (phosphorylation of tyrosine [Tyr] 416) in bone marrow MNCs of Gfi1 ϩ/ϩ and Gfi1 Ϫ/Ϫ mice, which was not modulated by G-CSF stimulation ( Figure 1F).…”

Section: Altered G-csf Signaling In Gfi1-deficient Hematopoietic Cellsmentioning

confidence: 99%

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

Sierra

Sakakibara

Gasperini

et al. 2010

Blood

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The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/ mitogen-activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis

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Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines

Cited by 145 publications

References 53 publications

The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation

The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation

RasMutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

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