Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB
Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB
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DOI：
10.1038/nature01811
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发表时间：
2003-08-14
期刊：
影响因子：
64.8
通讯作者：
Bernards, R
中科院分区：
文献类型：
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作者：
Brummelkamp, TR;Nijman, SMB;Bernards, R
通过泛素部分缀合的蛋白质修饰-泛素化-在许多生物学过程中起着重要作用，包括细胞周期和凋亡（1）。介导泛素缀合的酶已经被充分研究，但是关于介导细胞底物去泛素化的泛素特异性蛋白酶知之甚少（2，3）。为了研究这个基因家族，我们设计了一系列RNA干扰载体来抑制50种人类去泛素化酶，并使用这些载体来鉴定癌症相关通路中的去泛素化酶。我们在此报告，抑制这些酶之一，家族性圆柱瘤病肿瘤抑制基因（CYLD）（4），没有已知的功能，增强转录因子NF-κ B的激活。我们发现CYLD与IkappaB激酶（IKK）复合物的NEMO（也称为IKKgamma）组分结合，似乎通过TRAF 2的去泛素化来调节其活性，因为TRAF 2泛素化可以通过CYLD调节。CYLD的抑制增加了对细胞凋亡的抗性，表明CYLD的丢失有助于肿瘤发生的机制。我们发现，这种作用可以通过抑制NF-κ B活性的阿司匹林衍生物来缓解（5），这表明了一种治疗干预策略，可以恢复家族性圆柱瘤病患者的生长控制。
Protein modification by the conjugation of ubiquitin moieties-ubiquitination- plays a major part in many biological processes, including cell cycle and apoptosis(1). The enzymes that mediate ubiquitin-conjugation have been well-studied, but much less is known about the ubiquitin-specific proteases that mediate deubiquitination of cellular substrates(2,3). To study this gene family, we designed a collection of RNA interference vectors to suppress 50 human de-ubiquitinating enzymes, and used these vectors to identify de-ubiquitinating enzymes in cancer-relevant pathways. We report here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD)(4), having no known function, enhances activation of the transcription factor NF-kappaB. We show that CYLD binds to the NEMO (also known as IKKgamma) component of the IkappaB kinase (IKK) complex, and appears to regulate its activity through de-ubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. We show that this effect can be relieved by aspirin derivatives that inhibit NF-kappaB activity(5), which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.