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

Ingrid A. Mayer, Amit 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

126 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mayer, I. A., Verma, A., Grumbach, I. M., Uddin, S., Lekmine, F., Ravandi, F., Majchrzak, B., Fujita, S., Fish, E. N., & Platanias, L. C. (2001). The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells. Journal of Biological Chemistry, 276(30), 28570-28577. https://doi.org/10.1074/jbc.M011685200