Journal article
The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells
The Journal of biological chemistry, Vol.276(30), pp.28570-28577
07/2001
DOI: 10.1074/jbc.M011685200
PMID: 11353767
Abstract
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.
Details
- Title: Subtitle
- The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells
- Creators
- Ingrid A MayerAmit VermaIsabella M GrumbachShahab UddinFatima LekmineFarhad RavandiBeata MajchrzakShigeru FujitaEleanor N FishLeonidas C Platanias
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.276(30), pp.28570-28577
- DOI
- 10.1074/jbc.M011685200
- PMID
- 11353767
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Language
- English
- Date published
- 07/2001
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984094332402771
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