Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL

In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels...

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Bibliographic Details
Published in:Oncotarget 2015-06, Vol.6 (18), p.16559-16572
Main Authors: De Falco, Filomena, Sabatini, Rita, Del Papa, Beatrice, Falzetti, Franca, Di Ianni, Mauro, Sportoletti, Paolo, Baldoni, Stefano, Screpanti, Isabella, Marconi, Pierfrancesco, Rosati, Emanuela
Format: Article
Language:English
Subjects:
Apoptosis - genetics
Cell Survival - genetics
Eukaryotic Initiation Factor-4E - metabolism
Humans
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Myeloid Cell Leukemia Sequence 1 Protein - biosynthesis
Receptor, Notch1 - genetics
Receptor, Notch2 - genetics
Research Paper
RNA Interference
RNA, Small Interfering
Signal Transduction - genetics
Tumor Cells, Cultured
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Summary:In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.4116