Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition
| Autor: | Bart Vanhaesebroeck, Paul G. Tiffen, Tomoichiro Asano, Thomas G. Burdon, Antonio Bilancio, Kathrine Abell, Christine J. Watson, Anton I. Altaparmakov, Richard W. E. Clarkson |
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| Přispěvatelé: | Abell, K, Bilancio, Antonio, Clarkson, Rw, Tiffen, Pg, Altaparmakov, Ai, Burdon, Tg, Asano, T, Vanhaesebroeck, B, Watson, Cj |
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
STAT3 Transcription Factor
Programmed cell death Molecular Sequence Data Apoptosis Biology Protein Serine-Threonine Kinases Cell Line Mice Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins Animals STAT3 Protein kinase B Mammary gland involution Mice Knockout Kinase Epithelial Cells Cell Biology Molecular biology Mice Mutant Strains Cell biology DNA-Binding Proteins Protein Subunits biology.protein STAT protein Trans-Activators Chromatin immunoprecipitation Proto-Oncogene Proteins c-akt Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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