Bcr-Abl activates the AKT/Fox O3 signalling pathway to restrict transforming growth factor-beta-mediated cytostatic signals.
The fusion of Abl with either Bcr or Tel in human leukaemia leads to the constitutive activation of Abl tyrosine kinase, which in turn induces growth-factor-independent proliferation and cell survival. However, the mechanism by which Bcr-Abl induces cellular transformation has not yet been well characterized. Here, we show that Bcr-Abl-expressing cells are resistant to growth inhibition and apoptosis mediated by transforming growth factor-beta (TGF-beta). Interestingly, we observed that the suppressive effects of Bcr-Abl on TGF-beta responses were not mediated by an impairment of Smad signalling, which is believed to act as the principal mediator of TGF-beta responses. In contrast, we found that Bcr-Abl can target the protein kinase AKT and the transcription factor Fox O3 to interfere with growth inhibition and apoptosis in response to TGF-beta. Our results show a novel mechanism of cellular transformation by the oncogenic fusion protein Bcr-Abl through suppression of the cytostatic actions of TGF-beta.
Atfi
Azeddine
A
INSERM U482, 184 Rue du Faubourg St-Antoine, 75571 Paris, France. atfi@st-antoine.inserm.fr
Abécassis
Lucile
L
Bourgeade
Marie-Francoise
MF
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*
D051858:Forkhead Transcription Factors; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D051057:Proto-Oncogene Proteins c-akt