Tumor suppressor CYLD regulates JNK-Induced cell death in Drosophila
Tumor suppressor CYLD regulates JNK-Induced cell death in Drosophila
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DOI：
10.1016/j.devcel.2007.07.012
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发表时间：
2007-09-01
影响因子：
11.8
通讯作者：
Xu, Tian
中科院分区：
文献类型：
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作者：
Xue, Lei;Igaki, Tatsushi;Xu, Tian
CyLD编码一种肿瘤抑制基因，在家族性圆柱瘤病中发生突变。尽管进行了生化和细胞培养研究，但CyLD在动物发育和肿瘤发生中的生理功能仍然知之甚少。为了解决这些问题，我们培育了表达野生型和突变型dCyLD蛋白的突变型和转基因果蝇。在这里，我们证明了dCyLD对于JNK依赖的氧化应激抵抗和正常寿命是必不可少的。此外，dCyLD通过dTRAF2调节肿瘤坏死因子诱导的JNK激活和细胞死亡，dTRAF2作用于肿瘤坏死因子受体Wengen的下游和JNKK激酶dTAK1的上游。我们发现dCyLD编码一种去泛素化酶，使dTRAF2去泛素化，并阻止dTRAF2由泛素介导的蛋白质降解。这些数据为这种进化保守分子的肿瘤抑制功能提供了一个分子机制，表明dCyLD在调节肿瘤坏死因子-JNK介导的细胞死亡中起着关键作用。
CYLD encodes a tumor suppressor that is mutated in familial cylindromatosis. Despite biochemical and cell culture studies, the physiological functions of CYLD in animal development and tumorigenesis remain poorly understood. To address these questions, we generated Drosophila CYLD (dCYLD) mutant and transgenic flies expressing wild-type and mutant dCYLD proteins. Here we show that dCYLD is essential for JNK-dependent oxidative stress resistance and normal lifespan. Furthermore, dCYLD regulates TNF-induced JNK activation and cell death through dTRAF2, which acts downstream of the TNF receptor Wengen and upstream of the JNKK kinase dTAK1. We show that dCYLD encodes a deubiquitinating enzyme that deubiquitinates dTRAF2 and prevents dTRAF2 from ubiquitin-mediated proteolytic degradation. These data provide a molecular mechanism for the tumor suppressor function of this evolutionary conserved molecule by indicating that dCYLD plays a critical role in modulating TNF-JNK-mediated cell death.