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Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

Abstract

In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Abl-positive BV173 and BaF3/Bcr-Abl cells. Inhibition of Bcr-Abl kinase by STI571 results in FoxO3a activation, induction of Bim expression and apoptosis. Using reporter gene assays, we demonstrate that STI571 and FoxO3a activate Bim transcription through a FoxO-binding site (FHRE) located within the promoter. This was verified by DNA pull-down and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to induction of Bim expression and apoptosis. Conversely, silencing of FoxO3a in Bcr-Abl-expressing cells abolishes STI571-mediated Bim induction and apoptosis. Together, the results presented clearly confirm FoxO3a as a key regulator of apoptosis induced by STI571, and show that Bim is a direct transcriptional target of FoxO3a that mediates the STI571-induced apoptosis. Thus, STI571 induces an accumulation of FoxO3a activity which in turn binds directly to an FHRE in the promoter to activate Bim expression and apoptosis.

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Abbreviations

CML:

chronic myelogenous leukaemia

Ph:

Philadelphia chromosome

PI 3-K:

phosphatidylinositol 3-kinase

PKB:

protein kinase B

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

PBS:

phosphate-buffered salin

4-OHT:

4-hydroxytamoxifen

RT:

room tempertaure

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Acknowledgements

This research was supported by grants from the Leukaemia Research Fund-UK and CR UK. I Soeiro is supported by a PhD studentship from Fundação para a Ciência e a Tecnologia, Portugal, and A Essafi by a grant from the Algerian Government.

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Correspondence to Eric W-F Lam.

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Essafi, A., Fernández de Mattos, S., Hassen, Y. et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24, 2317–2329 (2005). https://doi.org/10.1038/sj.onc.1208421

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