F-box proteins FBXO31 and FBX4 in regulation of cyclin D1 degradation upon DNA damage.
F-box proteins FBXO31 and FBX4 in regulation of cyclin D1 degradation upon DNA damage.
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DOI：
10.1111/j.1755-148x.2009.00611.x
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发表时间：
2009-10
影响因子：
4.3
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Jia L;Sun Y
细胞周期进程受到细胞周期蛋白和细胞周期蛋白依赖性激酶（CDK）的精确调控，而CDK抑制剂（包括INK（如p16）和KIP（如p27）家族成员）对细胞周期进程产生负面影响。在正常细胞周期中，细胞周期蛋白D1（G1期进展的必需介质）由于促有丝分裂信号的转录激活而在中期G1期积累，而由于SCF E3泛素连接酶的靶向降解而在S期减少。SCF连接酶由Skp-1、Cullins、F-box蛋白和含有RING结构域的蛋白RBX 1/ROC 1或RBX 2/ROC 2/SAG组成，是最大的E3泛素连接酶，通过及时促进不同底物的降解来调节各种生物过程。在结构上，Cullin-1作为支架蛋白，其N-末端与Skp 1-F-box复合物结合，C-末端与RBX 1结合。核心SCF E3泛素是cullin和RBX 1的复合物; RBX 1结合E2并催化泛素从E2转移到底物。另一方面，SCF复合物的底物特异性由识别磷酸化底物以进行结合和随后降解的F盒蛋白决定。到目前为止，已经鉴定了三种F-box蛋白，FBX 031、FBX 4和FBXW 8，其与磷酸化细胞周期蛋白D1 Thr 286结合，用于响应DNA损伤和MAPK信号的靶向降解（Lin et al，2006; Okabe et al，2006; Pontano et al，2008; Santra et al，2009）。
Cell cycle progression is precisely regulated--positively by cyclins and cyclin dependent kinases (CDKs) and negatively by CDK inhibitors, consisting of INK (eg p16) and KIP (eg p27) family members. During a normal cell cycle, cyclin D1, an essential mediator of G1 phase progression, accumulates in mid-G1 phase as a result of transcriptional activation by mitogenic signals, whereas it decreases in S phase due to targeted degradation by SCF E3 ubiquitin ligases.SCF ligases, consisting of Skp-1, Cullins, F-box proteins and the RING domain containing protein RBX1/ROC1 or RBX2/ROC2/SAG, are the largest E3 ubiquitin ligases that regulate a variety of biological processes by timely promoting degradation of diverse substrates. Structurally, Cullin-1 acts as a scaffold protein, where its N-terminus binds to Skp1-F-box complex, and the C-terminus binds to RBX1. The core SCF E3 ubiquitin is the complex of cullins and RBX1; the latter binds to E2 and catalyzes the transfer of ubiquitin from E2 to substrates. The substrate specificity of SCF complex is, on the other hand, determined by F-box proteins that recognize phosphorylated substrates for binding and subsequent degradation. Up to the present, three F-box proteins, FBX031, FBX4, and FBXW8 have been identified to bind to phospho-cyclin D1Thr286 for targeted degradation in response to DNA damage and MAPK signals (Lin et al, 2006; Okabe et al, 2006; Pontano et al, 2008; Santra et al, 2009).