Nature Cell Biology7, 392 - 398 (2005)
Published online: 27 March 2005; | doi:10.1038/ncb1242
Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition
Kathrine Abell1, Antonio Bilancio2, Richard W. E. Clarkson1, Paul G. Tiffen1, Anton I. Altaparmakov1, Thomas G. Burdon3, Tomoichiro Asano4, Bart Vanhaesebroeck2, 5
& Christine J. Watson1
1
Mammary Apoptosis and Development Group, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK.
2
Cell Signalling Laboratory, Ludwig Institute for Cancer Research, London W1W 7BS, UK.
3
Roslin Institute, Roslin, Midlothian, EH25 9PS, UK.
4
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113, Japan.
5
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
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.
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and p50
