Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2391-2396 ◽  
Author(s):  
Olaf Witt ◽  
Katrin Sand ◽  
Arnulf Pekrun
Keyword(s):  
Signal Transduction ◽  
Map Kinase ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
P38 Map Kinase ◽  
Leukemia Cells ◽  
Common Mechanism ◽  
Signal Transduction Pathways ◽  
Human Leukemia ◽  
Mitogen Activated Protein

Butyrate induces cytodifferentiation in many tumor cells of different origin, suggesting that an as yet unidentified common mechanism inherent to malignant cells is the target of butyrate action. This study determined the role of different mitogen-activated protein (MAP) kinase signal transduction pathways in butyrate-induced erythroid differentiation of K562 human leukemia cells. Using a panel of anti-ERK, JNK, and p38 phosphospecific antibodies, the study showed that phosphorylation of ERK and JNK is decreased following treatment of cells with butyrate, whereas phosphorylation of p38 is increased. In contrast, a K562 subline defective in butyrate-mediated induction of erythroid differentiation did not reveal these changes in phosphorylation patterns. Inhibition of ERK activity by UO126 induces erythroid differentiation and acts synergistically with butyrate on hemoglobin synthesis and inhibition of cell proliferation, whereas inhibition of p38 activity by SB203580 completely abolished induction of hemoglobin expression by butyrate. Taken together, our data suggest a model in which butyrate induces erythroid differentiation of K562 cells by inhibition of ERK and activation of p38 signal transduction pathways.

Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2391-2396 ◽  
Author(s):  
Olaf Witt ◽  
Katrin Sand ◽  
Arnulf Pekrun
Keyword(s):  
Signal Transduction ◽  
Map Kinase ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
P38 Map Kinase ◽  
Leukemia Cells ◽  
Common Mechanism ◽  
Signal Transduction Pathways ◽  
Human Leukemia ◽  
Mitogen Activated Protein

Abstract Butyrate induces cytodifferentiation in many tumor cells of different origin, suggesting that an as yet unidentified common mechanism inherent to malignant cells is the target of butyrate action. This study determined the role of different mitogen-activated protein (MAP) kinase signal transduction pathways in butyrate-induced erythroid differentiation of K562 human leukemia cells. Using a panel of anti-ERK, JNK, and p38 phosphospecific antibodies, the study showed that phosphorylation of ERK and JNK is decreased following treatment of cells with butyrate, whereas phosphorylation of p38 is increased. In contrast, a K562 subline defective in butyrate-mediated induction of erythroid differentiation did not reveal these changes in phosphorylation patterns. Inhibition of ERK activity by UO126 induces erythroid differentiation and acts synergistically with butyrate on hemoglobin synthesis and inhibition of cell proliferation, whereas inhibition of p38 activity by SB203580 completely abolished induction of hemoglobin expression by butyrate. Taken together, our data suggest a model in which butyrate induces erythroid differentiation of K562 cells by inhibition of ERK and activation of p38 signal transduction pathways.

Signal transducer and activator of transcription 3 activation is required for Asp816 mutant c-Kit–mediated cytokine-independent survival and proliferation in human leukemia cells

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3559-3567 ◽  
Author(s):  
Zhi-Qiang Ning ◽  
Jin Li ◽  
Robert J. Arceci
Keyword(s):  
Signal Transduction ◽  
Dominant Negative ◽  
Leukemia Cells ◽  
Akt Pathway ◽  
Signal Transduction Pathways ◽  
Human Leukemia ◽  
Signal Transducer ◽  
Biologic Effects ◽  
Mitogen Activated Protein ◽  
Transcription 3

Activating mutations of c-kit at codon 816 (Asp816) have been implicated in a variety of malignancies, including acute myeloid leukemia (AML). The mutant c-Kit receptor confers cytokine-independent survival of leukemia cells and induces tumorigenicity. Changes in the signal transduction pathways responsible for Asp816 mutant c-Kit–mediated biologic effects are largely undefined. The results of this study show that Asp816 mutant c-Kit induces constitutive activation of signal transducer and activator of transcription 3 (STAT3) and STAT1, and up-regulates STAT3 downstream targets, Bcl-xL and c-myc. The phosphatidylinositol-3-kinase (PI-3K)/Akt pathway, but not the Ras-mediated mitogen-activated protein (MAP) kinase pathway, is also constitutively activated by Asp816 mutant c-Kit. Suppression of STAT3 activation by a dominant negative molecule in MO7e leukemia cells transduced with mutant c-kit inhibits stem cell factor (SCF)-independent survival and proliferation, accompanied by the down-regulation of Bcl-xL and c-myc. However, activated STAT3 does not appear to be the sole mediator that is responsible for the phenotypic changes induced by Asp816 mutant c-Kit, because expression of constitutively activated STAT3 in MO7e cells does not completely reconstitute cytokine independence. Activation of other signaling components by mutant c-Kit, such as those in the PI-3K/Akt pathway, is demonstrated and may also be needed for the mutant c-Kit–mediated biologic effects. The investigation of altered signal transduction pathways and the resulting functional consequences mediated by Asp816 mutant c-Kit should provide important information for the characterization of subsets of leukemia and potential molecular pathways for therapeutic targeting.

scholarly journals Apoptosis induced by erythroid differentiation of human leukemia cell lines is inhibited by Bcl-XL

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3837-3843 ◽  
Author(s):  
A Benito ◽  
M Silva ◽  
D Grillot ◽  
G Nunez ◽  
JL Fernandez-Luna
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Leukemia Cell ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Human Leukemia Cells ◽  
Leukemia Cell Lines ◽  
Wide Range

The induction of tumor cell differentiation represents an attractive strategy for the treatment of a wide range of malignancies. Differentiation of HL-60 promyelocytic leukemia cells towards neutrophils or monocytes has been shown to induce apoptotic cell death, which is inhibited by bcl-2 over-expression. However, the role of the bcl-2 gene family during erythroid differentiation of human leukemia cells remains unknown. We found that human erythroleukemia (HEL) and K562, two leukemia cell lines that undergo erythroid differentiation do not express Bcl-2, but express Bcl-XL, a related protein that functions as an inhibitor of apoptosis. Differentiation of HEL or K562 cells with inducers of erythroid differentiation (hemin, retinoic acid, or transforming growth factor-beta) was accompanied by progressive cell death and degradation of genomic DNA into oligonucleosomal fragments. The loss of cellular viability was associated with downregulation of bcl-xL mRNA and protein. In contrast, the levels of Bax, another Bcl-2 family member implicated in apoptosis remained unaltered. Constitutive expression of Bcl-XL by gene transfer inhibited apoptosis triggered by erythroid differentiation of HEL K562 cells. Yet, Bcl-XL did not alter the expression of epsilon-globin, which is induced during erythoid differentiation of HEL and K562 cells, arguing that apoptosis and differentiation can be uncoupled by Bcl-XL. These results indicate that Bcl-XL acts as an antiapoptosis protein in leukemia cells that undergo erythroid differentiation and that downregulation of bcl-x is a component of the apoptotic response that is coupled to differentiation in human leukemia cells.

Signal transduction pathways involved in the regulation of protein synthesis by insulin in L6 myoblasts

1998 ◽  
Vol 274 (1) ◽  
pp. C221-C228 ◽  
Author(s):  
Scot R. Kimball ◽  
Rick L. Horetsky ◽  
Leonard S. Jefferson
Keyword(s):  
Signal Transduction ◽  
Protein Synthesis ◽  
Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Signal Transduction Pathways ◽  
Ribosomal Protein S6 ◽  
Mitogen Activated Protein ◽  
Induced Changes ◽  
Stimulation Of

The phosphorylation states of three proteins implicated in the action of insulin on translation were investigated, i.e., 70-kDa ribosomal protein S6 kinase (p70 S6k ), eukaryotic initiation factor (eIF) 4E, and the eIF-4E binding protein 4E-BP1. Addition of insulin caused a stimulation of protein synthesis in L6 myoblasts in culture, an effect that was blocked by inhibitors of phosphatidylinositide-3-OH kinase (wortmannin), p70 S6k (rapamycin), and mitogen-activated protein kinase (MAP kinase) kinase (PD-98059). The stimulation of protein synthesis was accompanied by increased phosphorylation of p70 S6k , an effect that was blocked by rapamycin and wortmannin but not PD-98059. Insulin caused dephosphorylation of eIF-4E, an effect that appeared to be mediated by the p70 S6k pathway. Insulin also stimulated phosphorylation of 4E-BP1 as well as dissociation of the 4E-BP1 ⋅ eIF-4E complex. Both rapamycin and wortmannin completely blocked the insulin-induced changes in 4E-BP1 phosphorylation and association of 4E-BP1 and eIF-4E; PD-98059 had no effect on either parameter. Finally, insulin stimulated formation of the active eIF-4G ⋅ eIF-4E complex, an effect that was not prevented by any of the inhibitors. Overall, the results suggest that insulin stimulates protein synthesis in L6 myoblasts in part through utilization of both the p70 S6k and MAP kinase signal transduction pathways.

scholarly journals Induction of Interleukin-8 Synthesis Integrates Effects on Transcription and mRNA Degradation from at Least Three Different Cytokine- or Stress-Activated Signal Transduction Pathways

1999 ◽  
Vol 19 (10) ◽  
pp. 6742-6753 ◽  
Author(s):  
Helmut Holtmann ◽  
Reinhard Winzen ◽  
Pamela Holland ◽  
Solveig Eickemeier ◽  
Elke Hoffmann ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Map Kinase ◽  
Map Kinases ◽  
Interleukin 1 ◽  
Active Form ◽  
Mrna Degradation ◽  
P38 Map Kinase ◽  
Signal Transduction Pathways ◽  
Jnk Pathway ◽  
Map Kinase Kinase

ABSTRACT A hallmark of inflammation is the burst-like formation of certain proteins, initiated by cellular stress and proinflammatory cytokines like interleukin 1 (IL-1) and tumor necrosis factor, stimuli which simultaneously activate different mitogen-activated protein (MAP) kinases and NF-κB. Cooperation of these signaling pathways to induce formation of IL-8, a prototype chemokine which causes leukocyte migration and activation, was investigated by expressing active and inactive forms of protein kinases. Constitutively active MAP kinase kinase 7 (MKK7), an activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathway, induced IL-8 synthesis and transcription from a minimal IL-8 promoter. Furthermore, MKK7 synergized in both effects with NF-κB-inducing kinase (NIK). Activation of the IL-8 promoter by either of the kinases required functional NF-κB and AP-1 sites. While NIK and MKK7 did not affect degradation of IL-8 mRNA, an active form of MKK6, which selectively activates p38 MAP kinase, induced marked stabilization of the transcript and further increased IL-8 protein formation induced by NIK plus MKK7. Consistently, the MAP kinase kinase kinase MEKK1, which can activate NF-κB, SAPK/JNK, and p38 MAP kinases, most potently induced IL-8 formation. These results provide evidence that maximal IL-8 gene expression requires the coordinate action of at least three different signal transduction pathways which cooperate to induce mRNA synthesis and suppress mRNA degradation.

scholarly journals The Elk-1 ETS-Domain Transcription Factor Contains a Mitogen-Activated Protein Kinase Targeting Motif

1998 ◽  
Vol 18 (2) ◽  
pp. 710-720 ◽  
Author(s):  
Shen-Hsi Yang ◽  
Paula R. Yates ◽  
Alan J. Whitmarsh ◽  
Roger J. Davis ◽  
Andrew D. Sharrocks
Keyword(s):  
Signal Transduction ◽  
Map Kinase ◽  
Cellular Response ◽  
Map Kinases ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Common Mechanism ◽  
Mitogen Activated Protein

ABSTRACT The phosphorylation of transcription factors by mitogen-activated protein kinases (MAP) is a pivotal event in the cellular response to the activation of MAP kinase signal transduction pathways. Mitogenic and stress stimuli activate different pathways and lead to the activation of distinct groups of target proteins. Elk-1 is targeted by three distinct MAP kinase pathways. In this study, we demonstrate that the MAP kinase ERK2 is targeted to Elk-1 by a domain which is distinct from, and located N-terminally to, its phosphoacceptor motifs. Targeting via this domain is essential for the efficient and rapid phosphorylation of Elk-1 in vitro and full and rapid activation in vivo. Specific residues involved in ERK targeting have been identified. Our data indicate that the targeting of different classes of MAP kinases to their nuclear substrates may be a common mechanism to increase the specificity and efficiency of this signal transduction pathway.

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