The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells.

Mayer IA, Verma A, Grumbach IM, Uddin S, Lekmine F, Ravandi F, Majchrzak B, Fujita S, Fish EN, Platanias LC
J Biol Chem. 2001 276 (30): 28570-7

PMID: 11353767 · DOI:10.1074/jbc.M011685200

The mechanisms by which interferon-alpha (IFN-alpha) mediates its anti-leukemic effects in chronic myelogenous leukemia (CML) cells are not known. We determined whether p38 MAPK is activated by IFN-alpha in BCR-ABL-expressing cells and whether its function is required for the generation of growth inhibitory responses. IFN-alpha treatment induced phosphorylation/activation of p38 in the IFN-alpha-sensitive KT-1 cell line, but not in IFN-alpha-resistant K562 cells. Consistent with this, IFN-alpha 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-alpha-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-alpha signaling, the effects of pharmacological inhibition of p38 on the induction of IFN-alpha responses were determined. Treatment of KT-1 cells with the p38-specific inhibitors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-alpha. 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-alpha-dependent activation of p38 in the induction of the anti-leukemic effects of IFN-alpha, we evaluated the effects of p38 inhibition on leukemic colony formation in bone marrow samples of patients with CML. IFN-alpha 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-alpha in BCR-ABL-expressing cells and appears to play a key role in the generation of the growth inhibitory effects of IFN-alpha in CML cells.

MeSH Terms (23)

Androstadienes Cell Division Cell Line Dose-Response Relationship, Drug Electrophoresis, Polyacrylamide Gel Enzyme Activation Enzyme Inhibitors Fusion Proteins, bcr-abl Genistein Humans Imidazoles Immunoblotting Interferon-alpha Intracellular Signaling Peptides and Proteins K562 Cells MAP Kinase Signaling System Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases Phosphorylation Protein-Serine-Threonine Kinases Pyridines Tyrosine Wortmannin

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