ArticleOncogene2010
Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-gamma1-driven activation of mTOR/p70S6-kinase pathway.
Article in Oncogene, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 68 citations in OpenAlex.
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- Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma.The Journal of clinical investigation · 2023Article
- Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?International journal of molecular sciences · 2021Review
- The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines.Molecular biology reports · 2021Review
- Gene Transcription as a Therapeutic Target in Leukemia.International journal of molecular sciences · 2021Review
- Ponatinib Combined With Rapamycin Causes Regression of Murine Venous Malformation.Arteriosclerosis, thrombosis, and vascular biology · 2019Article
- The B cell receptor signaling pathway in mantle cell lymphoma.Oncotarget · 2018Review
- Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist.Translational psychiatry · 2018Article
- Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML.Oncotarget · 2017Article
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- Restricting the induction of NGF in ovarian stroma engenders selective follicular activation through the mTOR signaling pathway.Cell death & disease · 2017Article
- CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia.Oncotarget · 2017Article
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- Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
- Article
- Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1.American journal of physiology. Cell physiology · 2015Article
- Neuritic complexity of hippocampal neurons depends on WIP-mediated mTORC1 and Abl family kinases activities.Brain and behavior · 2015Article
- Epo-induced erythroid maturation is dependent on Plcγ1 signaling.Cell death and differentiation · 2015Article
- Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer.Cancer cell · 2014Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.