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Cell cycle Role of APC in cell cycle regulation


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Cell cycle Role of APC in cell cycle regulation

Role of APC in cell cycle regulation

Cell division progression is governed by degradation of different regulatory proteinsin the ubiquitin-dependent pathway. In this pathway, a polyubiquitin chain gets attachedto a protein substrate by an ubiquitin-ligase, which targets it for degradation by the26S proteasome. Anaphase-promoting complex ( APC ) is a one of ubiquitin ligases,which plays a key role in the cell cycle [1].

APC is mainly required to induce progression and exit from mitosis by inducingproteolysis of different cell cycle regulators. It contains its own catalytic core, butsubstrate recognition by APC is mediated by the APC activators, celldivision cycle 20 homolog ( CDC20) and fizzy/cell division cycle 20 related 1protein ( hCDH1 ). CDC20 activates APC mainly duringprophase-anaphase and hCDH1 activates APC mainly in mitotic exit and G1[1].

Phosphorylation of APC is one of the mechanisms used by the cell to modulateAPC activity. In this regard, three different kinases have been described tophosphorylate APC: cyclin-dependent kinase 1 ( CDK1 )/ Cyclin B,polo-like kinase 1 ( PLK1 ) and cAMP-dependent protein kinase ( PKA ). Thisphosphorylation modulates CDC20 binding to the APC and APC activity[1].

Existence and activity of APC/ APC activators complex also depends onregulation of activators . It is proposed that phosphorylation of CDC20 byCDK1 directly or indirectly (via PLK1 ) is required for CDC20-dependent APC activation [2] or for APC regulation of thespindle checkpoint [1].

In addition, CDC20 is also positively regulated by T-complex protein 1 (TCP1 ), which is known as a folding machine for actin and tubulin. TCP1 isessential for CDC20 -dependent cell cycle events such as sister chromatidseparation and exit from mitosis [3].

Two proteins of the spindle checkpoint, mitotic spindle assembly checkpoint proteins (MAD2 ) and budding uninhibited by benzimidazoles 1 homologues ( BUB ), arecapable of inhibiting APC/ CDC20 complex. Different studies havedemonstrated that this inhibition is mediated by direct binding of MAD2 andBUB to CDC20. In addition, MAD2b may inhibit APC/hCDK1 complex [4].

Besides the spindle checkpoint-dependent inhibitors of the APC, two other proteins,F-box protein 5 ( Emi1 ) [5] and Ras association domain familyprotein 1 ( RASSF1A ) [6], have been recently described as negativeregulators of this ubiquitin-ligase.

APC/ hCDK1 is inhibited by phosphorylation by CDK1/CyclinB or CDK2/ Cyclin A complexes during different cell cyclephases [7], [8]. The dephosphorylated hCDK1 binds toand activates APC [2]. Cell division cycle 14 homolog A (CDC14a ) is a major phosphatase for hCDH1 [9].

The activated APC/ hCDK1 and APC/ CDC20 complexesubiquitinate different substrates during different phases of cell cycle. Entry intoanaphase is marked by the initiation of sister chromatid separation. The APC-dependent degradation of pituitary tumor-transforming protein 1 ( Securin )participates in the cleavage of the cohesion complex, thereby allowing sister chromatidseparation [10]. Degradation of both Cyclin A and Cyclin B isalso required to induce sister chromatid disjunction. In addition, Cyclin Bproteolysis is required for inhibition of CDK1 activity followed by thedisassembly of the mitotic spindle, chromosome decondensation, cytokinesis andreformation of the nuclear envelope [1].

Moreover, Nek2A destruction in early mitosis is carried out by APC.Nek2A is a NIMA(never in mitosis gene a)-related kinase 2 implicated in regulatingcentrosome structure at the G2/M transition [11].

APC also induces degradation of several factors that are essential forspindle-pole separation and spindle disassembly. One of these factors is the kinesin-likeDNA-binding protein ( Kid ). It plays an important role in both meiotic andmitotic cell cycles. Degradation of KID is mediated by both and APC/ hCDH1and APC/ CDC20 complexes. It starts at anaphase and is maintained throughthe end of the G1 phase [12].

The main APC substrate during the G1 phase is the APC activator CDC20.CDC20 proteolysis by APC/ hCDH1 induces APC/ CDC20inactivation and allows a switch from APC/ CDC20 to APC/hCDH1 [13].

Besides CDC20, Aurora-A kinase is also degraded by the APCduring G1 phase. This proteolysis is exclusively mediated by APC/ hCDH1.Aurora A is localized to the spindles and its overexpression induces centrosomeduplication [14].

A recent report has identified a new G1 substrate of the APC, Tome-1,required for degradation of some protein kinases and for mitotic entry [15].In addition, Cdc25A degradation during mitotic exit and in early G1 is mediated bythe APC/ hCDH1 [16].

Three different APC substrates control DNA replication: ORC1 [17], CDC18L [18] and Geminin [18]. This control iscarried out by formation of the prereplication complex at the replication origins duringS phase.