Pathway Map Details

Cell cycle_Role of APC in cell cycle regulation



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Kid, PKA-cat (cAMP- dependent), RASSF1, CKS1, CDC14a, Geminin, CDC20, hCDH1, Aurora-A, MAD2a, Aurora-B, APC/CDC20 complex, Securin, BUB1, BUB3, CDK1 (p34), PLK1, APC/hCDH1 complex, ORC1L, CDK2, Tome-1, MAD2b, SKP2, CDC18L (CDC6), CDC25A, Anaphase-promoting complex (APC), Nek2A, Cyclin B, Cyclin A, TCP1, Emi1, BUBR1

Description:

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:

  1. Castro A, Bernis C, Vigneron S, Labbe JC, Lorca T
    The anaphase-promoting complex: a key factor in the regulation of cell cycle. Oncogene 2005 Jan 13;24(3):314-25
  2. Kotani S, Tanaka H, Yasuda H, Todokoro K
    Regulation of APC activity by phosphorylation and regulatory factors. The Journal of cell biology 1999 Aug 23;146(4):791-800
  3. Camasses A, Bogdanova A, Shevchenko A, Zachariae W
    The CCT chaperonin promotes activation of the anaphase-promoting complex through the generation of functional Cdc20. Molecular cell 2003 Jul;12(1):87-100
  4. Yu H
    Regulation of APC-Cdc20 by the spindle checkpoint. Current opinion in cell biology 2002 Dec;14(6):706-14
  5. Reimann JD, Freed E, Hsu JY, Kramer ER, Peters JM, Jackson PK
    Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell 2001 Jun 1;105(5):645-55
  6. Song MS, Song SJ, Ayad NG, Chang JS, Lee JH, Hong HK, Lee H, Choi N, Kim J, Kim H, Kim JW, Choi EJ, Kirschner MW, Lim DS
    The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex. Nature cell biology 2004 Feb;6(2):129-37
  7. Sorensen CS, Lukas C, Kramer ER, Peters JM, Bartek J, Lukas J
    A conserved cyclin-binding domain determines functional interplay between anaphase-promoting complex-Cdh1 and cyclin A-Cdk2 during cell cycle progression. Molecular and cellular biology 2001 Jun;21(11):3692-703
  8. Chen J, Fang G
    MAD2B is an inhibitor of the anaphase-promoting complex. Genes & development 2001 Jul 15;15(14):1765-70
  9. Bembenek J, Yu H
    Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14a. The Journal of biological chemistry 2001 Dec 21;276(51):48237-42
  10. Hagting A, Den Elzen N, Vodermaier HC, Waizenegger IC, Peters JM, Pines J
    Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. The Journal of cell biology 2002 Jun 24;157(7):1125-37
  11. Hames RS, Wattam SL, Yamano H, Bacchieri R, Fry AM
    APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box. The EMBO journal 2001 Dec 17;20(24):7117-27
  12. Castro A, Vigneron S, Bernis C, Labbe JC, Lorca T
    Xkid is degraded in a D-box, KEN-box, and A-box-independent pathway. Molecular and cellular biology 2003 Jun;23(12):4126-38
  13. Zachariae W, Nasmyth K
    Whose end is destruction: cell division and the anaphase-promoting complex. Genes & development 1999 Aug 15;13(16):2039-58
  14. Littlepage LE, Ruderman JV
    Identification of a new APC/C recognition domain, the A box, which is required for the Cdh1-dependent destruction of the kinase Aurora-A during mitotic exit. Genes & development 2002 Sep 1;16(17):2274-85
  15. Lim HH, Surana U
    Tome-1, wee1, and the onset of mitosis: coupled destruction for timely entry. Molecular cell 2003 Apr;11(4):845-6
  16. Donzelli M, Squatrito M, Ganoth D, Hershko A, Pagano M, Draetta GF
    Dual mode of degradation of Cdc25 A phosphatase. The EMBO journal 2002 Sep 16;21(18):4875-84
  17. Araki M, Wharton RP, Tang Z, Yu H, Asano M
    Degradation of origin recognition complex large subunit by the anaphase-promoting complex in Drosophila. The EMBO journal 2003 Nov 17;22(22):6115-26
  18. Petersen BO, Wagener C, Marinoni F, Kramer ER, Melixetian M, Lazzerini Denchi E, Gieffers C, Matteucci C, Peters JM, Helin K
    Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. Genes & development 2000 Sep 15;14(18):2330-43
  19. McGarry TJ, Kirschner MW
    Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 1998 Jun 12;93(6):1043-53