SCF(Skp2) 介导的 p27/p21 降解
中文名称
通路描述
在 G1 期，CDK 抑制剂（CKIs）p27 和 p21 通过抑制细胞周期依赖性激酶（CDKs）的活动来保持其活性，从而防止过早进入 S 期（见 Guardavaccaro 和 Pagano, 2006）。这两个 CKIs 在晚期 G1 期通过泛素化途径（Pagano 等人，1995；Bloom 等人，2003）被降解，涉及泛素化酶 SCF(Skp2)（Tsvetkov 等人，1999；Carrano 等人，1999；Sutterluty 等人，1999，Bornstein 等人，2003）和细胞周期调节蛋白 Cks1（Ganoth 等人，2001；Spruck 等人 2001；Bornstein 等人，2003）。SCF(Skp2) 识别 p27 并对其进行后续泛素化的过程依赖于 Cyclin E/A:Cdk2 介导的 p27 在 Thr 187 位点的磷酸化（Montagnoli 等人，1999）。有证据表明 Cyclin A/B:Cdk1 复合物也可以结合并磷酸化 p27 在 Th187 位点（Nakayama 等人，2004）。泛素化的多聚泛素化 p27 被 26S 蛋白酶体降解促进 CDKs 在驱动细胞进入 S 期的活动。SCF(Skp2) 介导的 p21 降解机制与 p27 类似，需要 Cks1 和 Cdk2/cyclin E/A 的存在（Bornstein 等人，2003；Wang 等人，2005）。此外，与 p27 观察到的类似，p21 在特定位点（Ser130）的磷酸化刺激其泛素化。与 p27 相反，p21 的泛素化可以在没有磷酸化的情况下发生，尽管效率较低（Bornstein 等人，2003）。SCF(Skp2) 介导的 p27/p21 降解从晚期 G1 期持续到 M 期。在 G0 和从早期 G1 到 G1/S 期，SCp2 被有丝分裂促进复合物/环化酶和激活因子 Cdh1 [APC/C(Cdh1)] 降解（Bashir 等人，2004；Wei 等人，2004）。APC/C(Cdh1) 活动的紧密调节确保及时消除 Skp2，从而在控制 G1/S 转换中发挥关键作用。APC/C(Cdh1) 在晚期 M 期通过未磷酸化的 Cdh1 与 APC/C 结合而激活。APC/C(Cdh1) 在 G1/S 期保持活性，此时它与抑制蛋白 Emi1 相互作用（Hsu 等人，2002）。抑制 APC/C(Cdh1) 活性导致 cyclins 积累，导致 Cdh1 的磷酸化，从而在 G1/S 期进一步抑制 Cdh1（Lukas 等人，1999）。最后，为了使 APC/C(Cdh1) 的失活永久化，Cdh1 及其 E2，即 Ubc10，在自泛素化事件中消除（Listovsky 等人，2004；Rape 和 Kirschner，2004）。在 G1/S 期，当 Cdh1 失活时，Skp2 重新积累，从而允许 p21 和 p27 的泛素化，导致 CDK 活性的进一步增加。
英文描述
SCF(Skp2)-mediated degradation of p27/p21 During G1, the activity of cyclin-dependent kinases (CDKs) is kept in check by the CDK inhibitors (CKIs) p27 and p21, thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). These two CKIs are degraded in late G1 phase by the ubiquitin pathway (Pagano et al., 1995; Bloom et al., 2003) involving the ubiquitin ligase SCF(Skp2) (Tsvetkov et al., 1999; Carrano et al., 1999; Sutterluty et al., 1999, Bornstein et al., 2003) and the cell-cycle regulatory protein Cks1 (Ganoth et al., 2001; Spruck et al 2001; Bornstein et al., 2003). Recognition of p27 by SCF(Skp2) and its subsequent ubiquitination is dependent upon Cyclin E/A:Cdk2- mediated phosphorylation at Thr 187 of p27 (Montagnoli et al., 1999). There is evidence that Cyclin A/B:Cdk1 complexes can also bind and phosphorylate p27 on Th187 (Nakayama et al., 2004). Degradation of polyubiquitinated p27 by the 26S proteasome promotes the activity of CDKs in driving cells into S phase. (Montagnoli et al., 1999; Tsvetkov et al., 1999, Carrano et al 1999). The mechanism of SCF(Skp2)-mediated degradation of p21 is similar to that of p27 in terms of its requirements for the presence of Cks1 and of Cdk2/cyclin E/A (Bornstein et al.,2003; Wang et al., 2005). In addition, as observed for p27, p21 phosphorylation at a specific site (Ser130) stimulates its ubiquitination. In contrast to p27, however, ubiquitination of p21 can take place in the absence of phosphorylation, although with less efficiency (Bornstein et al.,2003). SCF(Skp2)-mediated degradation of p27/p21 continues from late G1 through M-phase. During G0 and from early G1 to G1/S, Skp2 is degraded by the anaphase promoting complex/Cyclosome and its activator Cdh1 [APC/C(Cdh1)] (Bashir et al, 2004; Wei et al, 2004). The tight regulation of APC/C(Cdh1) activity ensures the timely elimination Skp2 and, thus, plays a critical role in controlling the G1/S transition. APC/C(Cdh1) becomes active in late M-phase by the association of unphosphorylated Cdh1 with the APC/C. APC/C(Cdh1) remains active until the G1/S phase at which time it interacts with the inhibitory protein, Emi1 (Hsu et al., 2002). Inhibition of APC/C(Cdh1) activity results in an accumulation of cyclins, which leads to the phosphorylation and consequently to a further inactivation of Cdh1 at G1/S (Lukas et al., 1999). Finally, to make the inactivation of APC/C(Cdh1) permanent, Cdh1 and its E2, namely Ubc10, are eliminated in an auto-ubiquitination event (Listovsky et al., 2004; Rape and Kirschner, 2004). At G1/S, Skp2 reaccumulates as Cdh1 is inactivated, thus allowing the ubiquitination of p21 and p27 and resulting in a further increase in CDK activity.
所含基因
50 个基因