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

被引:90
作者
Abell, K
Bilancio, A
Clarkson, RWE
Tiffen, PG
Altaparmakov, AI
Burdon, TG
Asano, T
Vanhaesebroeck, B
Watson, CJ
机构
[1] Univ Cambridge, Dept Pathol, Mammary Apoptosis & Dev Grp, Cambridge CB2 1QP, England
[2] Ludwig Inst Canc Res, Cell Signalling Lab, London W1W 7BS, England
[3] Roslin Inst, Roslin EH25 9PS, Midlothian, Scotland
[4] Univ Tokyo, Fac Med, Dept Internal Med 3, Tokyo 113, Japan
[5] UCL, Dept Biochem & Mol Biol, London WC1E 6BT, England
基金
英国生物技术与生命科学研究理事会;
关键词
D O I
10.1038/ncb1242
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Physiological apoptosis is induced by a switch from survival to death signalling. Dysregulation of this process is frequently associated with cancer(1). A powerful model for this apoptotic switch is mammary gland involution, during which redundant milk-producing epithelial cells undergo apoptosis(2). Signal transducer and activator of transcription 3 (Stat3) is an essential mediator of this switch but the mechanism has not yet been defined(3). 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) pathway(5). Here we show that expression of the PI(3) K regulatory subunits p55 alpha and p50 alpha is induced by Stat3 during involution. In the absence of Stat3 in vivo, upregulation of p55 alpha and p50 alpha is abrogated, levels of activated Akt are sustained and apoptosis is prevented. Chromatin immunoprecipitation assays show that Stat3 binds directly to the p55 alpha and p50 alpha promoters in vivo. Overexpression of either p55 alpha or p50 alpha 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.
引用
收藏
页码:392 / 398
页数:7
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