ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence.
ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence.
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ROC1/RBX1 E3泛素连接酶沉默通过顺序诱导G2-M停滞，凋亡和衰老来抑制肿瘤细胞的生长。
DOI：
10.1158/0008-5472.can-08-4671
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Sun, Yi
中科院分区：
文献类型：
--
作者：
Jia, Lijun;Soengas, Maria S.;Sun, Yi
ROC 1（Regulator of Cullins-1）或RBX 1（Ring Box Protein-1）是SCF（Skp-1，cullins，F-box proteins）E3泛素连接酶的RING组分，其通过靶向多种底物进行降解来调节多种细胞过程。然而，对ROC 1在人类癌症中的作用知之甚少。在这里，我们报道了ROC 1在原发性人类肿瘤组织和人类癌细胞系中普遍过表达。通过siRNA沉默ROC 1显著抑制多种人类癌细胞的生长，通过诱导衰老和凋亡以及G2/M期阻滞。衰老诱导以p53/p21和p16/pRB非依赖性方式与DNA损伤偶联。细胞凋亡与Puma的积累和Bcl-2、Mcl-1和存活素的减少相关; G2/M期阻滞与14-3-3σ的积累和细胞周期蛋白B1和Cdc 2的消除相关。在U87胶质母细胞瘤细胞中，这些表型变化在ROC 1沉默后依次发生，从G2/M停滞开始，随后是凋亡和衰老。因此，ROC 1沉默触发多个死亡和生长停滞途径，有效地抑制肿瘤细胞生长，表明ROC 1可能作为一个潜在的抗癌靶点。
ROC1 (Regulator of Cullins-1) or RBX1 (Ring Box Protein-1) is a RING component of SCF (Skp-1, cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting a variety of substrates for degradation. However, little is known about the role of ROC1 in human cancer. Here we reported that ROC1 is ubiquitously over-expressed in primary human tumor tissues and human cancer cell lines. ROC1 silencing by siRNA significantly inhibited the growth of multiple human cancer cells via induction of senescence and apoptosis as well as G2/M arrest. Senescence induction is coupled with DNA damage in p53/p21 and p16/pRB-independent manners. Apoptosis is associated with accumulation of Puma and reduction of Bcl-2, Mcl-1, and survivin; and G2/M arrest is associated with accumulation of 14-3-3σ and elimination of cyclin B1 and Cdc2. In U87 glioblastoma cells, these phenotypic changes occur sequentially upon ROC1 silencing, starting with G2/M arrest, followed by apoptosis and senescence. Thus, ROC1 silencing triggers multiple death and growth arrest pathways to effectively suppress tumor cell growth, suggesting that ROC1 may serve as a potential anti-cancer target.