PortalPublikationenNovel pathway in Bcr-Abl signal transduction involves Akt-in...

Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway

Standard

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, Jahrgang 29, Nr. 5, 04.02.2010, S. 739-51.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Markova, B, Albers, C, Breitenbuecher, F, Melo, JV, Brümmendorf, TH, Heidel, F, Lipka, D, Duyster, J, Huber, C & Fischer, T 2010, 'Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway', ONCOGENE, Jg. 29, Nr. 5, S. 739-51. https://doi.org/10.1038/onc.2009.374

APA

Markova, B., Albers, C., Breitenbuecher, F., Melo, J. V., Brümmendorf, T. H., Heidel, F., Lipka, D., Duyster, J., Huber, C., & Fischer, T. (2010). Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway. ONCOGENE, 29(5), 739-51. https://doi.org/10.1038/onc.2009.374

Vancouver

Markova B, Albers C, Breitenbuecher F, Melo JV, Brümmendorf TH, Heidel F et al. Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway. ONCOGENE. 2010 Feb 4;29(5):739-51. https://doi.org/10.1038/onc.2009.374

Bibtex

@article{dd037ab2f2fe4834b12d4d8d89b1f197,
title = "Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway",
abstract = "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.",
keywords = "Animals, Apoptosis, Benzamides, Blotting, Western, Enzyme Activation, Fusion Proteins, bcr-abl, Humans, Imatinib Mesylate, Intracellular Signaling Peptides and Proteins, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Phospholipase C gamma, Piperazines, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyrimidines, RNA, Small Interfering, Ribosomal Protein S6 Kinases, 70-kDa, Signal Transduction, TOR Serine-Threonine Kinases, Journal Article",
author = "B Markova and C Albers and F Breitenbuecher and Melo, {J V} and Br{\"u}mmendorf, {T H} and F Heidel and D Lipka and J Duyster and C Huber and Thomas Fischer",
year = "2010",
month = feb,
day = "4",
doi = "10.1038/onc.2009.374",
language = "English",
volume = "29",
pages = "739--51",
journal = "ONCOGENE",
issn = "0950-9232",
publisher = "NATURE PUBLISHING GROUP",
number = "5",

}

RIS

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 -