Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway
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Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway. / Markova, B; Albers, C; Breitenbuecher, F; Melo, J V; Brümmendorf, T H; Heidel, F; Lipka, D; Duyster, J; Huber, C; Fischer, Thomas.
In: ONCOGENE, Vol. 29, No. 5, 04.02.2010, p. 739-51.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway
AU - Markova, B
AU - Albers, C
AU - Breitenbuecher, F
AU - Melo, J V
AU - Brümmendorf, T H
AU - Heidel, F
AU - Lipka, D
AU - Duyster, J
AU - Huber, C
AU - Fischer, Thomas
PY - 2010/2/4
Y1 - 2010/2/4
N2 - In chronic myeloid leukemia, activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway is crucial for survival and proliferation of leukemic cells. Essential downstream molecules involve mammalian target of rapamycin (mTOR) and S6-kinase. Here, we present a comprehensive analysis of the molecular events involved in activation of these key signaling pathways. We provide evidence for a previously unrecognized phospholipase C-gamma1 (PLC-gamma1)-controlled mechanism of mTOR/p70S6-kinase activation, which operates in parallel to the classical Akt-dependent machinery. Short-term imatinib treatment of Bcr-Abl-positive cells caused dephosphorylation of p70S6-K and S6-protein without inactivation of Akt. Suppression of Akt activity alone did not affect phosphorylation of p70-S6K and S6. These results suggested the existence of an alternative mechanism for mTOR/p70S6-K activation. In Bcr-Abl-expressing cells, we detected strong PLC-gamma1 activation, which was suppressed by imatinib. Pharmacological inhibition and siRNA knockdown of PLC-gamma1 blocked p70S6-K and S6 phosphorylation. By inhibiting the Ca-signaling, CaMK and PKCs we demonstrated participation of these molecules in the pathway. Suppression of PLC-gamma1 led to inhibition of cell proliferation and enhanced apoptosis. The novel pathway proved to be essential for survival and proliferation of leukemic cells and almost complete cell death was observed upon combined PLC-gamma1 and Bcr-Abl inhibition. The pivotal role of PLC-gamma1 was further confirmed in a mouse leukemogenesis model.Oncogene advance online publication, 2 November 2009; doi:10.1038/onc.2009.374.
AB - In chronic myeloid leukemia, activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway is crucial for survival and proliferation of leukemic cells. Essential downstream molecules involve mammalian target of rapamycin (mTOR) and S6-kinase. Here, we present a comprehensive analysis of the molecular events involved in activation of these key signaling pathways. We provide evidence for a previously unrecognized phospholipase C-gamma1 (PLC-gamma1)-controlled mechanism of mTOR/p70S6-kinase activation, which operates in parallel to the classical Akt-dependent machinery. Short-term imatinib treatment of Bcr-Abl-positive cells caused dephosphorylation of p70S6-K and S6-protein without inactivation of Akt. Suppression of Akt activity alone did not affect phosphorylation of p70-S6K and S6. These results suggested the existence of an alternative mechanism for mTOR/p70S6-K activation. In Bcr-Abl-expressing cells, we detected strong PLC-gamma1 activation, which was suppressed by imatinib. Pharmacological inhibition and siRNA knockdown of PLC-gamma1 blocked p70S6-K and S6 phosphorylation. By inhibiting the Ca-signaling, CaMK and PKCs we demonstrated participation of these molecules in the pathway. Suppression of PLC-gamma1 led to inhibition of cell proliferation and enhanced apoptosis. The novel pathway proved to be essential for survival and proliferation of leukemic cells and almost complete cell death was observed upon combined PLC-gamma1 and Bcr-Abl inhibition. The pivotal role of PLC-gamma1 was further confirmed in a mouse leukemogenesis model.Oncogene advance online publication, 2 November 2009; doi:10.1038/onc.2009.374.
KW - Animals
KW - Apoptosis
KW - Benzamides
KW - Blotting, Western
KW - Enzyme Activation
KW - Fusion Proteins, bcr-abl
KW - Humans
KW - Imatinib Mesylate
KW - Intracellular Signaling Peptides and Proteins
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive
KW - Mice
KW - Phospholipase C gamma
KW - Piperazines
KW - Protein Kinase Inhibitors
KW - Protein-Serine-Threonine Kinases
KW - Proto-Oncogene Proteins c-akt
KW - Pyrimidines
KW - RNA, Small Interfering
KW - Ribosomal Protein S6 Kinases, 70-kDa
KW - Signal Transduction
KW - TOR Serine-Threonine Kinases
KW - Journal Article
U2 - 10.1038/onc.2009.374
DO - 10.1038/onc.2009.374
M3 - SCORING: Journal article
C2 - 19881535
VL - 29
SP - 739
EP - 751
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 5
ER -