Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells

Simrit Parmar, Efstratios Katsoulidis, Amit K. Verma, Yongzhong Li, Antonella Sassano, Lakhvir Lal, Beata Majchrzak, Farhad Ravandi, Martin S. Tallman, Eleanor N. Fish, Leonidas C. Platanias

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by ST1571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/ macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.

Original languageEnglish (US)
Pages (from-to)25345-25352
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number24
DOIs
StatePublished - Jun 11 2004
Externally publishedYes

Fingerprint

Cohort Effect
p38 Mitogen-Activated Protein Kinases
Chemical activation
Emitter coupled logic circuits
KT 1
Protein-Tyrosine Kinases
Phosphotransferases
Granulocyte-Macrophage Progenitor Cells
Phosphorylation
Imatinib Mesylate
Macrophages
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Growth
Mitogen-Activated Protein Kinases
Protein Kinases
Leukemia
Stem Cells
Cells
Pharmacology
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells. / Parmar, Simrit; Katsoulidis, Efstratios; Verma, Amit K.; Li, Yongzhong; Sassano, Antonella; Lal, Lakhvir; Majchrzak, Beata; Ravandi, Farhad; Tallman, Martin S.; Fish, Eleanor N.; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 279, No. 24, 11.06.2004, p. 25345-25352.

Research output: Contribution to journalArticle

Parmar, S, Katsoulidis, E, Verma, AK, Li, Y, Sassano, A, Lal, L, Majchrzak, B, Ravandi, F, Tallman, MS, Fish, EN & Platanias, LC 2004, 'Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells', Journal of Biological Chemistry, vol. 279, no. 24, pp. 25345-25352. https://doi.org/10.1074/jbc.M400590200
Parmar, Simrit ; Katsoulidis, Efstratios ; Verma, Amit K. ; Li, Yongzhong ; Sassano, Antonella ; Lal, Lakhvir ; Majchrzak, Beata ; Ravandi, Farhad ; Tallman, Martin S. ; Fish, Eleanor N. ; Platanias, Leonidas C. / Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 24. pp. 25345-25352.
@article{abce49112ec1484eb553db0fbbc30988,
title = "Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells",
abstract = "Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by ST1571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/ macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.",
author = "Simrit Parmar and Efstratios Katsoulidis and Verma, {Amit K.} and Yongzhong Li and Antonella Sassano and Lakhvir Lal and Beata Majchrzak and Farhad Ravandi and Tallman, {Martin S.} and Fish, {Eleanor N.} and Platanias, {Leonidas C.}",
year = "2004",
month = "6",
day = "11",
doi = "10.1074/jbc.M400590200",
language = "English (US)",
volume = "279",
pages = "25345--25352",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "24",

}

TY - JOUR

T1 - Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells

AU - Parmar, Simrit

AU - Katsoulidis, Efstratios

AU - Verma, Amit K.

AU - Li, Yongzhong

AU - Sassano, Antonella

AU - Lal, Lakhvir

AU - Majchrzak, Beata

AU - Ravandi, Farhad

AU - Tallman, Martin S.

AU - Fish, Eleanor N.

AU - Platanias, Leonidas C.

PY - 2004/6/11

Y1 - 2004/6/11

N2 - Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by ST1571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/ macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.

AB - Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by ST1571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/ macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.

UR - http://www.scopus.com/inward/record.url?scp=2942558439&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2942558439&partnerID=8YFLogxK

U2 - 10.1074/jbc.M400590200

DO - 10.1074/jbc.M400590200

M3 - Article

C2 - 15056660

AN - SCOPUS:2942558439

VL - 279

SP - 25345

EP - 25352

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 24

ER -