Document Detail


Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells.
MedLine Citation:
PMID:  15688014     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Abdelkader Essafi; Silvia Fernández de Mattos; Yasmin A M Hassen; Inês Soeiro; Ghulam J Mufti; N Shaun B Thomas; René H Medema; Eric W-F Lam
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncogene     Volume:  24     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-03-31     Completed Date:  2005-04-18     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  2317-29     Citation Subset:  IM    
Affiliation:
Cancer Research-UK labs, Department of Cancer Medicine, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Apoptosis Regulatory Proteins
Base Sequence
Carrier Proteins / genetics*
Cell Line
Cell Line, Tumor
DNA
DNA-Binding Proteins / physiology*
Forkhead Transcription Factors
Fusion Proteins, bcr-abl / metabolism*
Humans
Membrane Proteins / genetics*
Mice
Molecular Sequence Data
Piperazines / pharmacology*
Promoter Regions, Genetic
Proto-Oncogene Proteins / genetics*
Pyrimidines / pharmacology*
RNA, Small Interfering
Transcription Factors / physiology*
Transcription, Genetic / physiology*
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/Carrier Proteins; 0/DNA-Binding Proteins; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Fusion Proteins, bcr-abl; 0/Membrane Proteins; 0/Piperazines; 0/Proto-Oncogene Proteins; 0/Pyrimidines; 0/RNA, Small Interfering; 0/Transcription Factors; 152459-95-5/imatinib; 9007-49-2/DNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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