Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition

Kathrine Abell, Antonio Bilancio, Richard W E Clarkson, Paul G Tiffen, Anton I Altaparmakov, Tom Burdon, Tomoichiro Asano, Bart Vanhaesebroeck, Christine J Watson

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)392-8
Number of pages7
JournalNature Cell Biology
Volume7
Issue number4
Publication statusPublished - Apr 2005

Keywords

  • Animals
  • Apoptosis/physiology
  • Cell Line
  • DNA-Binding Proteins/metabolism
  • Epithelial Cells/metabolism
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases/genetics
  • Phosphatidylinositol 3-Kinases/metabolism
  • 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

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