Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition
Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition
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DOI：
10.1038/ncb1242
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发表时间：
2005-04-01
影响因子：
21.3
通讯作者：
Watson, CJ
中科院分区：
文献类型：
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作者：
Abell, K;Bilancio, A;Watson, CJ
生理性细胞凋亡是由从生存到死亡信号传导的转换诱导的。这一过程的失调通常与癌症有关（1）。这种凋亡开关的一个强有力的模型是乳腺退化，在此期间，多余的产奶上皮细胞发生凋亡（2）。信号转导子和转录激活子3（Stat 3）是这种转换的重要介质，但其机制尚未确定（3）。退化过程中Stat 3依赖性细胞死亡可通过激活Akt/蛋白激酶B（PKB）（4）（磷酸肌醇-3-OH激酶（PI（3）K）途径的下游效应物）（5）来阻断。在这里，我们表明PI（3）K调节亚基p55 α和p50 α的表达是由Stat 3在退化过程中诱导的。在体内不存在Stat 3的情况下，p55 α和p50 α的上调被废除，活化Akt的水平被维持，并且细胞凋亡被阻止。染色质免疫沉淀分析表明，Stat 3直接结合到p55 α和p50 α启动子在体内。p55 α或p50 α的过表达降低了活化Akt的水平。我们提出了一种新的机制，其中Stat 3通过诱导不同的PI（3）K调节亚基的表达下调PI（3）K-Akt介导的生存信号来调节凋亡。
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.