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EMBO reports 6, 10, 985–991 (2005)
doi:10.1038/sj.embor.7400501
Published online: 19 August 2005
Bcr–Abl activates the AKT/FoxO3 signalling pathway to restrict transforming growth factor- -mediated cytostatic signals
Azeddine Atfi1, Lucile Abécassis2 & Marie-Francoise Bourgeade2
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1 INSERM U482, 184 Rue du Faubourg St-Antoine, 75571 Paris, France
2 INSERM U 542, 14 Avenue PV Couturier, 94807 Villejuif, France
To whom correspondence should be addressed
Azeddine Atfi Tel: +1 33 49 28 46 11; Fax: +1 33 40 19 90 62; E-mail: atfi@st-antoine.inserm.fr
Received 10 January 2005; Accepted 7 July 2005; Published online 19 August 2005.
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Abstract
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- (TGF-). Interestingly, we observed that the suppressive effects of Bcr–Abl on TGF- responses were not mediated by an impairment of Smad signalling, which is believed to act as the principal mediator of TGF- responses. In contrast, we found that Bcr–Abl can target the protein kinase AKT and the transcription factor FoxO3 to interfere with growth inhibition and apoptosis in response to TGF-. Our results show a novel mechanism of cellular transformation by the oncogenic fusion protein Bcr–Abl through suppression of the cytostatic actions of TGF-.
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