PTEN Loss Promotes Mitochondrially Dependent Type II Fas-Induced Apoptosis via PEA-15
PTEN Loss Promotes Mitochondrially Dependent Type II Fas-Induced Apoptosis via PEA-15
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DOI：
10.1128/mcb.01660-08
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发表时间：
2009-03-01
影响因子：
5.3
通讯作者：
Ong, Christopher J.
中科院分区：
文献类型：
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作者：
Peacock, James W.;Palmer, Jodie;Ong, Christopher J.
CD95/Fas死亡受体传递两种不同的生化信号。线粒体独立（I型）和线粒体依赖（II型）Fas凋亡途径差异的分子基础尚不清楚。通过分析24个Fas敏感的肿瘤系，我们现在证明PTEN肿瘤抑制因子的表达/活性与不同的Fas信号密切相关。PTEN功能丧失和功能获得的研究证明了在I型和II型Fas通路之间相互转换的能力。重要的是，从Bcl-2转基因Pten（+/-）小鼠的分析中，Pten单倍不足将fas诱导的凋亡从Bcl-2非依赖性转化为Bcl-2敏感性。我们进一步表明，PTEN至少在一定程度上通过调节PEA-15的磷酸化和活性来影响Fas信号传导，而PEA-15的磷酸化和活性反过来又调节Bcl-2抑制Fas诱导的凋亡的能力。因此，PTEN是一个关键的分子变换器，它决定细胞在Fas刺激下是通过线粒体独立的I型还是线粒体依赖的II型凋亡途径死亡。
Two distinct biochemical signals are delivered by the CD95/Fas death receptor. The molecular basis for the differential mitochondrially independent (type I) and mitochondrially dependent (type II) Fas apoptosis pathways is unknown. By analyzing 24 Fas-sensitive tumor lines, we now demonstrate that expression/activity of the PTEN tumor suppressor strongly correlates with the distinct Fas signals. PTEN loss-of-function and gain-of-function studies demonstrate the ability to interconvert between type I and type II Fas pathways. Importantly, from analyses of Bcl-2 transgenic Pten(+/-) mice, Pten haploinsufficiency converts Fas-induced apoptosis from a Bcl-2-independent to a Bcl-2-sensitive response in primary thymocytes and activated T lymphocytes. We further show that PTEN influences Fas signaling, at least in part, by regulating PEA-15 phosphorylation and activity that, in turn, regulate the ability of Bcl-2 to suppress Fas-induced apoptosis. Thus, PTEN is a key molecular rheostat that determines whether a cell dies by a mitochondrially independent type I versus a mitochondrially dependent type II apoptotic pathway upon Fas stimulation.