The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells

Ingrid A. Mayer, Amit K. Verma, Isabella M. Grumbach, Shahab Uddin, Fatima Lekmine, Farhad Ravandi, Beata Majchrzak, Shigeru Fujita, Eleanor N. Fish, Leonidas C. Platanias

Research output: Contribution to journalArticle

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Abstract

The mechanisms by which interferon-α (IFN-α) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-α in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-α treatment induced phosphorylation/activation of p38 in the IFN-α-sensitive KT-1 cell line, but not in IFN-α-resistant K562 cells. Consistent with this, IFN-α treatment of KT-1 (but not K562) cells induced activation of the small GTPase Rac1, which functions as an upstream regulator of p38. In addition, IFN-α-dependent phosphorylation/activation of p38 was induced by treatment of primary granulocytes isolated from the peripheral blood of patients with CML. To define the functional role of the Rac1/p38 MAPK pathway in IFN-α signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-α responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-α. On the other hand, the MEK kinase inhibitor PD098059 had no effects, further demonstrating the specificity of these findings. To directly determine the significance of IFN-α-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-α, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-α inhibited leukemic granulocyte/macrophage colony formation in a dose-dependent manner, whereas concomitant treatment with p38 inhibitors reversed such an inhibition. Thus, the Rac1/p38 MAPK pathway is activated by IFN-α in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-α in CML cells.

Original languageEnglish (US)
Pages (from-to)28570-28577
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number30
DOIs
StatePublished - Jul 27 2001
Externally publishedYes

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p38 Mitogen-Activated Protein Kinases
Interferons
Growth
KT 1
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Chemical activation
Phosphorylation
K562 Cells
Granulocytes
MAP Kinase Kinase Kinases
Therapeutics
Monomeric GTP-Binding Proteins
Macrophages
Bone

ASJC Scopus subject areas

  • Biochemistry

Cite this

The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells. / Mayer, Ingrid A.; Verma, Amit K.; Grumbach, Isabella M.; Uddin, Shahab; Lekmine, Fatima; Ravandi, Farhad; Majchrzak, Beata; Fujita, Shigeru; Fish, Eleanor N.; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 276, No. 30, 27.07.2001, p. 28570-28577.

Research output: Contribution to journalArticle

Mayer, IA, Verma, AK, Grumbach, IM, Uddin, S, Lekmine, F, Ravandi, F, Majchrzak, B, Fujita, S, Fish, EN & Platanias, LC 2001, 'The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells', Journal of Biological Chemistry, vol. 276, no. 30, pp. 28570-28577. https://doi.org/10.1074/jbc.M011685200
Mayer, Ingrid A. ; Verma, Amit K. ; Grumbach, Isabella M. ; Uddin, Shahab ; Lekmine, Fatima ; Ravandi, Farhad ; Majchrzak, Beata ; Fujita, Shigeru ; Fish, Eleanor N. ; Platanias, Leonidas C. / The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 30. pp. 28570-28577.
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abstract = "The mechanisms by which interferon-α (IFN-α) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-α in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-α treatment induced phosphorylation/activation of p38 in the IFN-α-sensitive KT-1 cell line, but not in IFN-α-resistant K562 cells. Consistent with this, IFN-α treatment of KT-1 (but not K562) cells induced activation of the small GTPase Rac1, which functions as an upstream regulator of p38. In addition, IFN-α-dependent phosphorylation/activation of p38 was induced by treatment of primary granulocytes isolated from the peripheral blood of patients with CML. To define the functional role of the Rac1/p38 MAPK pathway in IFN-α signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-α responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-α. On the other hand, the MEK kinase inhibitor PD098059 had no effects, further demonstrating the specificity of these findings. To directly determine the significance of IFN-α-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-α, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-α inhibited leukemic granulocyte/macrophage colony formation in a dose-dependent manner, whereas concomitant treatment with p38 inhibitors reversed such an inhibition. Thus, the Rac1/p38 MAPK pathway is activated by IFN-α in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-α in CML cells.",
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AU - Verma, Amit K.

AU - Grumbach, Isabella M.

AU - Uddin, Shahab

AU - Lekmine, Fatima

AU - Ravandi, Farhad

AU - Majchrzak, Beata

AU - Fujita, Shigeru

AU - Fish, Eleanor N.

AU - Platanias, Leonidas C.

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N2 - The mechanisms by which interferon-α (IFN-α) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-α in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-α treatment induced phosphorylation/activation of p38 in the IFN-α-sensitive KT-1 cell line, but not in IFN-α-resistant K562 cells. Consistent with this, IFN-α treatment of KT-1 (but not K562) cells induced activation of the small GTPase Rac1, which functions as an upstream regulator of p38. In addition, IFN-α-dependent phosphorylation/activation of p38 was induced by treatment of primary granulocytes isolated from the peripheral blood of patients with CML. To define the functional role of the Rac1/p38 MAPK pathway in IFN-α signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-α responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-α. On the other hand, the MEK kinase inhibitor PD098059 had no effects, further demonstrating the specificity of these findings. To directly determine the significance of IFN-α-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-α, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-α inhibited leukemic granulocyte/macrophage colony formation in a dose-dependent manner, whereas concomitant treatment with p38 inhibitors reversed such an inhibition. Thus, the Rac1/p38 MAPK pathway is activated by IFN-α in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-α in CML cells.

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