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

Abell, Kathrine, Bilancio, Antonio, Clarkson, Richard W. E., Tiffen, Paul G., Altaparmakov, Anton I., Burdon, Thomas G., Asano, Tomoichiro, Vanhaesebroeck, Bart and Watson, Christine J. 2005. Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Nature Cell Biology Vol. 7 (4) , pp. 392-398. 10.1038/ncb1242

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Abstract

Physiological apoptosis is induced by a switch from survival to death signalling. Dysregulation of this process is frequently associated with cancer1. A powerful model for this apoptotic switch is mammary gland involution, during which redundant milk-producing epithelial cells undergo apoptosis2. Signal transducer and activator of transcription 3 (Stat3) is an essential mediator of this switch but the mechanism has not yet been defined3. Stat3-dependent cell death during involution can be blocked by activation of Akt/protein kinase B (PKB)4, a downstream effector of the phosphoinositide-3-OH kinase (PI(3)K) pathway5. Here we show that expression of the PI(3)K regulatory subunits p55? and p50? is induced by Stat3 during involution. In the absence of Stat3 in vivo, upregulation of p55? and p50? is abrogated, levels of activated Akt are sustained and apoptosis is prevented. Chromatin immunoprecipitation assays show that Stat3 binds directly to the p55? and p50? promoters in vivo. Overexpression of either p55? or p50? 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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
ISSN: 1465-7392
Last Modified: 04 Jun 2017 01:37
URI: http://orca.cf.ac.uk/id/eprint/1008

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