Caspase inhibition blocks cell death and enhances mitophagy but fails to promote T-cell lymphoma.
Caspase inhibition blocks cell death and enhances mitophagy but fails to promote T-cell lymphoma.
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DOI：
10.1371/journal.pone.0019786
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Knudson CM
中科院分区：
文献类型：
--
作者：
Wang SH;Martin SM;Harris PS;Knudson CM
Caspase-9是凋亡体的一个组成部分，介导细胞色素c从线粒体释放后的细胞死亡。Casp9DN抑制Caspase-9的显性阴性结构（Casp9DN）可阻断凋亡功能，促进细胞活力，并与癌变有关。体外抑制细胞凋亡损害线粒体功能，促进线粒体自噬。为了研究抑制凋亡是否会增强线粒体自噬并促进体内肿瘤的发生，我们在T细胞谱系中产生了表达Casp9DN的转基因小鼠。观察Casp9DN对胸腺细胞活力、有丝分裂和胸腺肿瘤形成的影响。在原代胸腺细胞中，Casp9DN延缓了地塞米松（Dex）诱导的细胞死亡，改变了线粒体结构，减少了氧化剂的产生。透射电镜（TEM）显示，抑制凋亡导致线粒体结构异常，在某些情况下，线粒体被类似自噬体的双膜结构吞没。与线粒体被自噬体吞噬（线粒体吞噬）一致，共聚焦显微镜显示LC3-GFP和线粒体共定位。然而，Casp9DN单独或与Lck-Bax38/1或Beclin 1+/−小鼠（两种易患肿瘤的菌株，线粒体功能改变与促进肿瘤发展有关）并没有显著加速t细胞淋巴瘤的发生。此外，Beclin 1的杂合破坏对Lck-Bax38/1小鼠t细胞淋巴瘤的形成没有影响。进一步的研究表明Beclin 1水平对casp9dn诱导的线粒体功能丧失没有影响。这些结果表明，抑制凋亡功能和Beclin 1单倍不足都不会加速小鼠t细胞淋巴瘤的发展。
Caspase-9 is a component of the apoptosome that mediates cell death following release of cytochrome c from mitochondria. Inhibition of Caspase-9 with a dominant negative construct (Casp9DN) blocks apoptosome function, promotes viability and has been implicated in carcinogenesis. Inhibition of the apoptosome in vitro impairs mitochondrial function and promotes mitophagy. To examine whether inhibition of the apoptosome would enhance mitophagy and promote oncogenesis in vivo, transgenic mice were generated that express Casp9DN in the T cell lineage. The effects of Casp9DN on thymocyte viability, mitophagy and thymic tumor formation were examined. In primary thymocytes, Casp9DN delayed dexamethasone (Dex)-induced cell death, altered mitochondrial structure, and decreased oxidant production. Transmission electron microscopy (TEM) revealed that inhibition of the apoptosome resulted in structurally abnormal mitochondria that in some cases were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitochondria being engulfed by autophagosomes (mitophagy), confocal microscopy showed colocalization of LC3-GFP and mitochondria. However, Casp9DN did not significantly accelerate T-cell lymphoma alone, or in combination with Lck-Bax38/1, or with Beclin 1+/− mice, two tumor-prone strains in which altered mitochondrial function has been implicated in promoting tumor development. In addition, heterozygous disruption of Beclin 1 had no effect on T-cell lymphoma formation in Lck-Bax38/1 mice. Further studies showed that Beclin 1 levels had no effect on Casp9DN-induced loss of mitochondrial function. These results demonstrate that neither inhibition of apoptosome function nor Beclin 1 haploinsufficiency accelerate T-cell lymphoma development in mice.
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影响因子：
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