Intrinsic and extrinsic pathway signaling during neuronal apoptosis: lessons from the analysis of mutant mice.
Intrinsic and extrinsic pathway signaling during neuronal apoptosis: lessons from the analysis of mutant mice.
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DOI：
10.1083/jcb.200110108
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发表时间：
2002-04-29
期刊：
影响因子：
--
通讯作者：
Johnson EM Jr
中科院分区：
文献类型：
--
作者：
Putcha GV;Harris CA;Moulder KL;Easton RM;Thompson CB;Johnson EM Jr
营养因子剥夺(TFD)诱导的交感神经细胞凋亡需要依赖大分子合成的Bax易位、细胞色素c(Cytc)释放和caspase激活。在这里，我们报告了其他内在和外在途径信号对这些过程的贡献。交感神经元表达所有抗凋亡的bcl2蛋白，但仅表达特定的BH3和多结构域促凋亡的bcl2家族成员。然而，所有共表达的促凋亡蛋白都没有表现出功能冗余或代偿性表达，至少在所研究的bax−/−、bak−/−、bim−/−、Bid−/−和Bad−/−神经元中是这样。尽管某些bcl2蛋白的亚细胞分布或翻译后修饰随着TFD的变化而改变，但在这种范例中，转录或翻译后机制都不能调控BID、BAD或BAK的表达或亚细胞定位。尽管Fas和FasL的表达被适度诱导，但Fas介导的信号转导并不参与TFD诱导的交感神经元的凋亡。在K+戒断诱导的小脑颗粒神经元凋亡中也得到了类似的发现，这是中枢神经系统中活动依赖的神经元存活的模型。因此，单靠表达并不能保证bcl2家族成员之间的功能冗余(或补偿)，而且，至少在一些细胞中，外部途径信号和某些仅BH3蛋白(即Bid和Bad)不能促进TFD引起的Bax依赖的Cytc释放或凋亡。
Trophic factor deprivation (TFD)-induced apoptosis in sympathetic neurons requires macromolecular synthesis–dependent BAX translocation, cytochrome c (cyt c) release, and caspase activation. Here, we report the contributions of other intrinsic and extrinsic pathway signals to these processes. Sympathetic neurons expressed all antiapoptotic BCL-2 proteins examined, yet expressed only certain BH3-only and multidomain proapoptotic BCL-2 family members. All coexpressed proapoptotic proteins did not, however, exhibit functional redundancy or compensatory expression, at least in the Bax −/−, Bak −/−, Bim −/−, Bid −/−, and Bad −/− neurons examined. Although the subcellular distribution or posttranslational modification of certain BCL-2 proteins changed with TFD, neither transcriptional nor posttranslational mechanisms regulated the expression or subcellular localization of BID, BAD, or BAK in this paradigm. Despite modest induction of Fas and FasL expression, Fas-mediated signaling did not contribute to TFD-induced apoptosis in sympathetic neurons. Similar findings were obtained with K+ withdrawal–induced apoptosis in cerebellar granule neurons, a model for activity-dependent neuronal survival in the CNS. Thus, expression alone does not guarantee functional redundancy (or compensation) among BCL-2 family members, and, at least in some cells, extrinsic pathway signaling and certain BH3-only proteins (i.e., BID and BAD) do not contribute to BAX-dependent cyt c release or apoptosis caused by TFD.
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