Mdm2介导的p53的NEDD8缀合抑制其转录活性。

Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity.

作者信息

Xirodimas Dimitris P, Saville Mark K, Bourdon Jean-Christophe, Hay Ronald T, Lane David P

机构信息

University of Dundee, Ninewells Hospital and Medical School, Department of Surgery and Molecular Oncology, Dundee DD1 9SY, UK.

出版信息

Cell. 2004 Jul 9;118(1):83-97. doi: 10.1016/j.cell.2004.06.016.

DOI:10.1016/j.cell.2004.06.016

PMID:15242646

Abstract

The only reported role for the conjugation of the NEDD8 ubiquitin-like molecule is control of the activity of SCF ubiquitin ligase complexes. Here, we show that the Mdm2 RING finger E3 ubiquitin ligase can also promote NEDD8 modification of the p53 tumor suppressor protein. Mdm2 is itself modified with NEDD8 with very similar characteristics to the autoubiquitination activity of Mdm2. By using a cell line (TS-41) with a temperature-sensitive mutation in the NEDD8 conjugation pathway and a p53 mutant that cannot be NEDDylated (3NKR), we demonstrate that Mdm2-dependent NEDD8 modification of p53 inhibits its transcriptional activity. These findings expand the role for Mdm2 as an E3 ligase, providing evidence that Mdm2 is a common component of the ubiquitin and NEDD8 conjugation pathway and indicating the diverse mechanisms by which E3 ligases can control the function of substrate proteins.

摘要

已报道的NEDD8类泛素分子缀合的唯一作用是控制SCF泛素连接酶复合物的活性。在此，我们表明Mdm2环指E3泛素连接酶也能促进p53肿瘤抑制蛋白的NEDD8修饰。Mdm2自身被NEDD8修饰，其特征与Mdm2的自身泛素化活性非常相似。通过使用在NEDD8缀合途径中具有温度敏感突变的细胞系（TS-41）和不能被NEDD化的p53突变体（3NKR），我们证明Mdm2依赖的p53的NEDD8修饰会抑制其转录活性。这些发现扩展了Mdm2作为E3连接酶的作用，提供了证据表明Mdm2是泛素和NEDD8缀合途径的共同组分，并表明E3连接酶控制底物蛋白功能的多种机制。