Skp2 knockout reduces cell proliferation and mouse body size: and prevents cancer?
Skp2 knockout reduces cell proliferation and mouse body size: and prevents cancer?
复制标题
作者：
将多个泛素（一种在真核细胞中普遍表达的76个残基的蛋白质）共价连接到蛋白质上，标记该蛋白质在蛋白酶体（一种被认为是蛋白质降解工厂的大型隧道样复合物）中降解。有许多类型的泛素连接酶（进行蛋白质泛素化反应的酶）;其中之一是Culin-RING泛素连接酶（CRL）。Culin-RING共有6种蛋白和2种蛋白，构成了6种通用的Culin-RING核心平台，为各种底物募集亚基完成底物特异性CRL的形成。SCF型CRL由Rbx 1（RING蛋白）、Skp 1、Cul 1和F-box蛋白形成。F-box蛋白使用它们的F-box序列结合Skp 1，Skp 1反过来将F-box蛋白带到Cul 1。人体内大约有70种F盒蛋白，其中之一是Skp 2。特定F盒蛋白的名称在SCF后用上标书写，如SCFSkp 2中。SCFSkp 2的最佳研究底物是细胞周期蛋白依赖性激酶抑制剂p27 Kip 1。为了使SCFSkp 2介导p27泛素化，p27必须首先在Thr 187（T187）上磷酸化，并且还必须存在辅助蛋白Cks 1。因此，该反应可称为SCFSkp 2/Cks 1-p27 T187 p机制;该复合物的X射线晶体结构显示了p27 T187磷酸化的结构要求[1]。除了p27之外，Skp 2还被报道介导大约30种其他蛋白的泛素化[2]。产生Skp 2敲除小鼠（Skp 2-/-小鼠）以确定Skp 2的生理作用[3]。来自Skp 2-/-胚胎和Skp 2-/-小鼠的许多器官的小鼠胚胎成纤维细胞（MEF）含有增加水平的p27蛋白，表明Skp 2确实在p27蛋白降解中起重要作用。Skp 2-/-MEF在培养物中增殖极其缓慢，并且与Skp 2 +/+同窝出生小鼠相比，Skp 2-/-小鼠约小25%，表明Skp 2具有所需的一般增殖促进功能。Skp 2-/-MEFs和Skp 2-/-小鼠的这些缺陷可以通过联合敲除p27来纠正，表明p27是Skp 2的主要靶点。这种Skp 2-p27关系立即表明了以下情况。作为细胞周期蛋白依赖性激酶的抑制剂，p27可能是一种肿瘤抑制因子。事实上，p27蛋白水平在癌细胞中通常降低，并且更大的p27降低通常与更差的肿瘤相关。由于Skp 2对抗p27（通过靶向其降解），Skp 2被怀疑是一种癌蛋白。事实上，Skp 2蛋白水平在癌细胞中通常会增加，尤其是在p27蛋白减少的细胞中，并且较高的Skp 2蛋白水平通常预示着较差的预后。p27敲除或Skp 2的异位表达可促进许多小鼠肿瘤模型中的肿瘤发生。下一个未回答的问题是Skp 2敲除是否可以抑制肿瘤发生。由于Skp 2敲除可以抑制正常增殖（Skp 2-/-MEFs增殖极差，Skp 2-/-小鼠明显更小），因此可能在Skp 2-/-MEFs和Skp 2-/-小鼠中也会抑制癌基因诱导的异常增殖。另一方面，Skp 2-/-MEFs和Skp 2-/-小鼠也含有增加的细胞周期蛋白E蛋白和扩大的细胞核;这些特性将有利于肿瘤发生。在《自然》杂志最近的一篇文章中，林和他的同事直接回答了这个问题。他们报告了戏剧性的数据显示，响应于各种致癌信号（激活的Ras的异位表达，Ras与腺病毒癌蛋白E1 A的异位表达，肿瘤抑制因子Pten的敲除或肿瘤抑制因子ARF的敲除），Skp 2-/-MEFs......
Attaching multiple ubiquitins (a 76-residue protein ubiquitously expressed in eukaryotic cells) covalently to a protein labels that protein for degradation in the proteasome (a large tunnel-like complex considered as a protein degradation factory). There are many types of ubiquitin ligases (the enzymes that carry out the protein ubiquitination reactions); one of them is the Culin-RING ubiquitin ligase (CRL). There are six Culin proteins and two RING proteins, forming six general types of Culin-RING core platforms for various substraterecruiting subunits to complete the formation of substrate-specific CRLs. The SCF type CRL is formed with Rbx1 (a RING protein), Skp1, Cul1, and an F-box protein. F-box proteins use their F-box sequences to bind Skp1, which, in turn, brings the F-box protein to Cul1. There are about seventy F-box proteins in humans; one of them is Skp2. The name of the specific F-box protein is written in superscript after SCF as in SCFSkp2. The best-studied substrate of SCFSkp2 is the cyclin-dependent kinase inhibitor p27Kip1. For SCFSkp2 to mediate p27 ubiquitination, p27 must first be phosphorylated on Thr187 (T187) and an auxiliary protein Cks1 must also be present. This reaction therefore can be called the SCFSkp2/Cks1-p27T187p mechanism; X-ray crystal structure of this complex shows the structural requirement for phosphorylation of p27T187 [1]. In addition to p27, Skp2 has been reported to mediate ubiquitination of about thirty other proteins [2]. Skp2 knockout mice (Skp2–/–mice) were generated to determine the physiological roles of Skp2 [3]. Mouse embryo fibroblasts (MEFs) derived from Skp2–/–embryos and a number of organs in Skp2–/–mice contain increased levels of p27 protein, indicating that Skp2 indeed plays important roles in p27 protein degradation. Skp2–/–MEFs proliferate extremely slowly in culture and Skp2–/–mice are about 25% smaller compared with Skp2+/+ littermates, indicating that Skp2 has a required general proliferation-promoting function. These defects of Skp2–/–MEFs and Skp2–/–mice can be corrected by combined knockout of p27, indicating that p27 is the major target of Skp2. This Skp2-p27 relationship immediately suggested the following. As an inhibitor of cyclin-dependent kinases, p27 is a suspected tumor suppressor. Indeed, p27 protein levels are often reduced in cancer cells and greater p27 reductions often correlate with poorer prognoses. Since Skp2 counters p27 (by targeting it for degradation), Skp2 is suspected to be an oncoprotein. Indeed, Skp2 protein levels are often increased in cancer cells, especially in cells with reduced p27 protein, and higher Skp2 protein levels often predict poorer prognoses. p27 knockout or ectopic expression of Skp2 could promote tumorigenesis in a number of mouse tumor models. The next unanswered question was whether Skp2 knockout could inhibit tumorigenesis. Since Skp2 knockout can inhibit normal proliferation (Skp2–/–MEFs proliferate extremely poorly and Skp2–/–mice are significantly smaller), it is likely that oncogene-induced abnormal proliferation would also be inhibited in Skp2–/–MEFs and in Skp2–/–mice. On the other hand, Skp2–/–MEFs and Skp2–/–mice also contain increased cyclin E proteins and enlarged nuclei; these properties would favor tumorigenesis. In a recent article in Nature [4], Lin and colleagues directly addressed this question. They report dramatic data showing that, in response to various oncogenic signals (ectopic expression of an activated Ras, ectopic expression of Ras together with an adenovirus oncoprotein E1A, knockout of the tumor suppressor Pten, or knockout of the tumor suppressor ARF), Skp2–/–MEFs …
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16
作者：
Hao, B;Zheng, N;Pavletich, NP
通讯作者：
Pavletich, NP
DOI：
10.1158/1541-7786.mcr-09-0232
发表时间：
2010-03
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Old JB;Kratzat S;Hoellein A;Graf S;Nilsson JA;Nilsson L;Nakayama KI;Peschel C;Cleveland JL;Keller UB
通讯作者：
Keller UB
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Malek, NP;Sundberg, H;Roberts, JM
通讯作者：
Roberts, JM