Document Detail

Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition.
MedLine Citation:
PMID:  15793565     Owner:  NLM     Status:  MEDLINE    
Physiological apoptosis is induced by a switch from survival to death signalling. Dysregulation of this process is frequently associated with cancer. A powerful model for this apoptotic switch is mammary gland involution, during which redundant milk-producing epithelial cells undergo apoptosis. Signal transducer and activator of transcription 3 (Stat3) is an essential mediator of this switch but the mechanism has not yet been defined. Stat3-dependent cell death during involution can be blocked by activation of Akt/protein kinase B (PKB), a downstream effector of the phosphoinositide-3-OH kinase (PI(3)K) pathway. Here we show that expression of the PI(3)K regulatory subunits p55alpha and p50alpha is induced by Stat3 during involution. In the absence of Stat3 in vivo, upregulation of p55alpha and p50alpha is abrogated, levels of activated Akt are sustained and apoptosis is prevented. Chromatin immunoprecipitation assays show that Stat3 binds directly to the p55alpha and p50alpha promoters in vivo. Overexpression of either p55alpha or p50alpha reduces levels of activated Akt. We propose a novel mechanism in which Stat3 regulates apoptosis by inducing expression of distinct PI(3)K regulatory subunits to downregulate PI(3)K-Akt-mediated survival signalling.
Kathrine Abell; Antonio Bilancio; Richard W E Clarkson; Paul G Tiffen; Anton I Altaparmakov; Thomas G Burdon; Tomoichiro Asano; Bart Vanhaesebroeck; Christine J Watson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-03-27
Journal Detail:
Title:  Nature cell biology     Volume:  7     ISSN:  1465-7392     ISO Abbreviation:  Nat. Cell Biol.     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-01     Completed Date:  2005-05-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100890575     Medline TA:  Nat Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  392-8     Citation Subset:  IM    
Mammary Apoptosis and Development Group, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AC107662;  AK046259;  U50413;  U50414
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / genetics,  metabolism*
Apoptosis / physiology*
Cell Line
DNA-Binding Proteins / metabolism*
Epithelial Cells / metabolism
Mice, Knockout
Mice, Mutant Strains
Molecular Sequence Data
Protein Subunits / metabolism
Protein-Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
STAT3 Transcription Factor
Signal Transduction / physiology
Trans-Activators / metabolism*
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Protein Subunits; 0/Proto-Oncogene Proteins; 0/STAT3 Transcription Factor; 0/Stat3 protein, mouse; 0/Trans-Activators; EC 3-Kinase; EC Kinases; EC Proteins c-akt

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