GILZ inhibits the mTORC2/AKT pathway in ...
Document type :
Article dans une revue scientifique
DOI :
PMID :
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Title :
GILZ inhibits the mTORC2/AKT pathway in BCR-ABL(+) cells
Author(s) :
Joha, S [Auteur]
Nugues, A-L [Auteur]
Hetuin, D [Auteur]
Berthon, C [Auteur]
Dezitter, Xavier [Auteur]
Dauphin, V [Auteur]
Mahon, F-X [Auteur]
Roche-Lestienne, C [Auteur]
Preudhomme, C [Auteur]
Quesnel, Bruno [Auteur]
Idziorek, Thierry [Auteur]
Nugues, A-L [Auteur]
Hetuin, D [Auteur]
Berthon, C [Auteur]
Dezitter, Xavier [Auteur]
Dauphin, V [Auteur]
Mahon, F-X [Auteur]
Roche-Lestienne, C [Auteur]
Preudhomme, C [Auteur]
Quesnel, Bruno [Auteur]
Idziorek, Thierry [Auteur]
Journal title :
Oncogene
Abbreviated title :
Oncogene
Volume number :
31
Pages :
1419-1430
Publication date :
2012-03-01
English keyword(s) :
dasatinib
imatinib
BCR-ABL
mTORC2
AKT
GILZ
imatinib
BCR-ABL
mTORC2
AKT
GILZ
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide ...
Show more >The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide 3-kinase/AKT, signal transducer and activator of transcription 5 and extracellular signal-regulated kinase 1/2. In patients with CML, tyrosine kinase inhibitors (TKIs) are used to suppress the BCR-ABL tyrosine kinase, resulting in impressive response rates. However, resistance can occur, especially in acute-phase CML, through various mechanisms. Here, we show that the glucocorticoid-induced leucine zipper protein (GILZ) modulates imatinib and dasatinib resistance and suppresses tumor growth by inactivating the mammalian target of rapamycin complex-2 (mTORC2)/AKT signaling pathway. In mouse and human models, GILZ binds to mTORC2, but not to mTORC1, inhibiting phosphorylation of AKT (at Ser473) and activating FoxO3a-mediated transcription of the pro-apoptotic protein Bim; these results demonstrate that GILZ is a key inhibitor of the mTORC2 pathway. Furthermore, CD34(+) stem cells isolated from relapsing CML patients underwent apoptosis and showed inhibition of mTORC2 after incubation with glucocorticoids and imatinib. Our findings provide new mechanistic insights into the role of mTORC2 in BCR-ABL(+) cells and indicate that regulation by GILZ may influence TKI sensitivity.Show less >
Show more >The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide 3-kinase/AKT, signal transducer and activator of transcription 5 and extracellular signal-regulated kinase 1/2. In patients with CML, tyrosine kinase inhibitors (TKIs) are used to suppress the BCR-ABL tyrosine kinase, resulting in impressive response rates. However, resistance can occur, especially in acute-phase CML, through various mechanisms. Here, we show that the glucocorticoid-induced leucine zipper protein (GILZ) modulates imatinib and dasatinib resistance and suppresses tumor growth by inactivating the mammalian target of rapamycin complex-2 (mTORC2)/AKT signaling pathway. In mouse and human models, GILZ binds to mTORC2, but not to mTORC1, inhibiting phosphorylation of AKT (at Ser473) and activating FoxO3a-mediated transcription of the pro-apoptotic protein Bim; these results demonstrate that GILZ is a key inhibitor of the mTORC2 pathway. Furthermore, CD34(+) stem cells isolated from relapsing CML patients underwent apoptosis and showed inhibition of mTORC2 after incubation with glucocorticoids and imatinib. Our findings provide new mechanistic insights into the role of mTORC2 in BCR-ABL(+) cells and indicate that regulation by GILZ may influence TKI sensitivity.Show less >
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
CHU Lille
Inserm
Université de Lille
Inserm
Université de Lille
Collections :
Research team(s) :
Therapeutic innovation targetting inflammation
Submission date :
2019-05-17T13:08:47Z
2021-05-28T09:09:27Z
2021-05-28T09:09:27Z