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Details on Person During G1, the activity of cyclin-dependent kinases (CDKs) i...
| Class:Id | Summation:187576 |
|---|---|
| _displayName | During G1, the activity of cyclin-dependent kinases (CDKs) i... |
| _timestamp | 2011-12-22 15:20:18 |
| created | [InstanceEdit:187578] Matthews, L, 2006-09-20 13:07:27 |
| literatureReference | [LiteratureReference:187842] Stabilizers and destabilizers controlling cell cycle oscillators [LiteratureReference:187850] Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27 [LiteratureReference:187825] Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation [LiteratureReference:187523] p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27 [LiteratureReference:187517] SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 [LiteratureReference:187818] p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells [LiteratureReference:187544] The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27 [LiteratureReference:187837] A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1 [LiteratureReference:187515] Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation [LiteratureReference:187801] Skp2-mediated degradation of p27 regulates progression into mitosis [LiteratureReference:187793] Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection [LiteratureReference:187848] Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase [LiteratureReference:187864] Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex [LiteratureReference:176432] E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1) [LiteratureReference:174194] Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex [LiteratureReference:176906] Mammalian Cdh1/Fzr mediates its own degradation [LiteratureReference:187863] Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry |
| modified | [InstanceEdit:187582] Matthews, L, 2006-09-20 14:12:48 [InstanceEdit:187867] Matthews, L, 2006-09-28 02:40:37 [InstanceEdit:2026108] Orlic-Milacic, M, 2011-12-22 |
| text | 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. |
| (summation) | [Pathway:187577] SCF(Skp2)-mediated degradation of p27/p21 [Homo sapiens] |
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