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 .
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 .
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 .
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  or for
APC regulation of the spindle checkpoint .
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 .
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
Besides the spindle checkpoint-dependent inhibitors of the APC, two other proteins,
F-box protein 5 (Emi1)  and Ras association
domain family protein 1
(RASSF1A) , have been
recently described as negative regulators of this ubiquitin-ligase.
inhibited by phosphorylation by
CDK2/Cyclin A complexes during different cell
cycle phases , .
The dephosphorylated hCDK1 binds to and
activates APC . Cell division cycle 14
homolog A (CDC14a) is a major
phosphatase for hCDH1 .
The activated APC/hCDK1 and
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 .
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
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 .
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 .
The main APC substrate during the G1 phase is the APC
activator CDC20. CDC20
proteolysis by APC/hCDH1
inactivation and allows a switch from
APC/ CDC20 to
Besides CDC20, Aurora-A
kinase is also degraded by the APC during G1 phase. This
proteolysis is exclusively mediated by
A is localized to the spindles and its overexpression induces centrosome
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 . In addition,
Cdc25A degradation during mitotic exit and in early G1 is
mediated by the APC/hCDH1
Three different APC substrates control DNA replication:
ORC1 , CDC18L
 and Geminin . This control
is carried out by formation of the prereplication complex at the replication origins
during S phase.
- 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
- 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
- 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
- Yu H
Regulation of APC-Cdc20 by the spindle checkpoint.
Current opinion in cell biology 2002 Dec;14(6):706-14
- 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
- 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
- S?rensen 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
- Chen J, Fang G
MAD2B is an inhibitor of the anaphase-promoting complex.
Genes & development 2001 Jul 15;15(14):1765-70
- 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
- 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
- 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
- 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
- Zachariae W, Nasmyth K
Whose end is destruction: cell division and the anaphase-promoting complex.
Genes & development 1999 Aug 15;13(16):2039-58
- 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
- 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
- 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
- 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
- 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
- McGarry TJ, Kirschner MW
Geminin, an inhibitor of DNA replication, is degraded during mitosis.
Cell 1998 Jun 12;93(6):1043-53