TY - JOUR
T1 - The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells
AU - Mayer, Ingrid A.
AU - Verma, Amit
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.
PY - 2001/7/27
Y1 - 2001/7/27
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0035958901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035958901&partnerID=8YFLogxK
U2 - 10.1074/jbc.M011685200
DO - 10.1074/jbc.M011685200
M3 - Article
C2 - 11353767
AN - SCOPUS:0035958901
SN - 0021-9258
VL - 276
SP - 28570
EP - 28577
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 30
ER -