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 proteins in the ubiquitin-dependent pathway. In this pathway, a polyubiquitin chain gets attached to a protein substrate by an ubiquitin-ligase, which targets it for degradation by the 26S 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 inducing proteolysis of different cell cycle regulators. It contains its own catalytic core, but substrate recognition by APC is mediated by the APC activators, cell division cycle 20 homolog (CDC20) and fizzy/cell division cycle 20 related 1 protein (hCDH1). CDC20 activates APC mainly during prophase-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 modulate APC activity. In this regard, three different kinases have been described to phosphorylate APC: cyclin-dependent kinase 1 (CDK1)/Cyclin B, polo-like kinase 1 (PLK1) and cAMP-dependent protein kinase (PKA). This phosphorylation modulates CDC20 binding to the APC and APC activity [1].

Existence and activity of APC/APC activators complex also depends on regulation of activators. It is proposed that phosphorylation of CDC20 by CDK1 directly or indirectly (via PLK1) is required for CDC20-dependent APC activation [2] or for APC regulation of the spindle 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 is essential for CDC20-dependent cell cycle events such as sister chromatid separation 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), are capable of inhibiting APC/CDC20 complex. Different studies have demonstrated that this inhibition is mediated by direct binding of MAD2 and BUB 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 family protein 1 (RASSF1A) [6], have been recently described as negative regulators of this ubiquitin-ligase.

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

The activated APC/hCDK1 and APC/CDC20 complexes ubiquitinate different substrates during different phases of cell cycle. Entry into anaphase 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 chromatid separation [10]. Degradation of both Cyclin A and Cyclin B is also required to induce sister chromatid disjunction. In addition, Cyclin B proteolysis is required for inhibition of CDK1 activity followed by the disassembly of the mitotic spindle, chromosome decondensation, cytokinesis and reformation 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 regulating centrosome structure at the G2/M transition [11].

APC also induces degradation of several factors that are essential for spindle-pole separation and spindle disassembly. One of these factors is the kinesin-like DNA-binding protein (Kid). It plays an important role in both meiotic and mitotic cell cycles. Degradation of KID is mediated by both and APC/hCDH1 and APC/CDC20 complexes. It starts at anaphase and is maintained through the 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/CDC20 inactivation and allows a switch from APC/ CDC20 to APC/hCDH1 [13].

Besides CDC20, Aurora-A kinase is also degraded by the APC during G1 phase. This proteolysis is exclusively mediated by APC/hCDH1. Aurora A is localized to the spindles and its overexpression induces centrosome duplication [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 by the APC/hCDH1 [16].

Three different APC substrates control DNA replication: ORC1 [17], CDC18L [18] and Geminin [19]. This control is carried out by formation of the prereplication complex at the replication origins during S phase.

References:

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