瘤抑制剂CYLD通过二基因化对NF-kappaB信号进行负面调节
Andrew Kovalenko1, Christine Chable-Bessia, Giuseppina Cantarella
1Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Nature
|August 15, 2003
概括
作为一种瘤抑制剂的CYLD通过使IKK复杂成分脱化来调节NF-kappaB信号传递. 在CYLD中发生的突变会损害这种功能,将duebiquitination与家族式圆柱体瘤的病理生理学联系起来.
科学领域:
- 细胞生物学 细胞生物学
- 疾病的分子机制.
- 瘤抑制功能的功能
背景情况:
- NF-kappaB转录因子调节关键的细胞过程,包括炎症,免疫反应和瘤发生.
- NF-kappaB活性由细胞质抑制剂 (IkappaB) 严格控制,并由IkappaB激酶 (IKK) 复合体调节.
- NF-kappaB信号的失调与各种疾病有关,包括癌症和炎症疾病.
研究的目的:
- 研究瘤抑制剂CYLD在NF-kappaB信号调节中的作用.
- 阐明CYLD与IKK复合体相互作用和调节的分子机制.
- 建立CYLD的酶活性与其在人类病理生理学中的作用之间的联系,特别是家族性圆柱体瘤.
主要方法:
- 同免疫沉试验用于研究CYLD,NEMO和TRAF2.2之间的蛋白质与蛋白质相互作用.
- 试验室二化试验以表征CYLD在聚化链上的酶活性.
- 分析了在家族性圆柱状瘤中发现的CYLD断层,以评估它们对酶功能的影响.
- 评估CYLD对TRAF介导的IKK激活的调制.
主要成果:
- CYLD 直接与 IKK 综合体的子单元 NEMO 和关键信号适配器 TRAF2 相互作用.
- CYLD具有非K48连接的多联链的特异性去联活动.
- CYLD对IKK复合体的TRAF介导激活产生负面调节.
- 在家族性圆柱形肌病中发现的CYLD的截断形式显示出降低了deubiquitinating活性.
结论:
- CYLD作为NF-kappaB信号传递的负调节器,通过对IKK激活通路的组件进行脱.
- 在TRAF介导的IKK激活中,ubiquitination起着至关重要的作用,这是由CYLD调节的过程.
- 由于突变导致的CYLD的双化活性受损与家族式圆柱状瘤病理生理学有关.
相关概念视频
01:23Negative Regulator Molecules
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
02:26NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
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