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Review
. 2014 Jan;1843(1):150-62.
doi: 10.1016/j.bbamcr.2013.02.028. Epub 2013 Mar 1.

The Ubiquitin Proteasome System - Implications for Cell Cycle Control and the Targeted Treatment of Cancer

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Free PMC article
Review

The Ubiquitin Proteasome System - Implications for Cell Cycle Control and the Targeted Treatment of Cancer

Florian Bassermann et al. Biochim Biophys Acta. .
Free PMC article

Abstract

Two families of E3 ubiquitin ligases are prominent in cell cycle regulation and mediate the timely and precise ubiquitin-proteasome-dependent degradation of key cell cycle proteins: the SCF (Skp1/Cul1/F-box protein) complex and the APC/C (anaphase promoting complex or cyclosome). While certain SCF ligases drive cell cycle progression throughout the cell cycle, APC/C (in complex with either of two substrate recruiting proteins: Cdc20 and Cdh1) orchestrates exit from mitosis (APC/C(Cdc20)) and establishes a stable G1 phase (APC/C(Cdh1)). Upon DNA damage or perturbation of the normal cell cycle, both ligases are involved in checkpoint activation. Mechanistic insight into these processes has significantly improved over the last ten years, largely due to a better understanding of APC/C and the functional characterization of multiple F-box proteins, the variable substrate recruiting components of SCF ligases. Here, we review the role of SCF- and APC/C-mediated ubiquitylation in the normal and perturbed cell cycle and discuss potential clinical implications of SCF and APC/C functions. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

Keywords: APC/C; Cancer; Cell cycle; F-box; SCF complex; Ubiquitin proteasome system.

Figures

Figure 1
Figure 1. Structure of the SCF and the APC/C ubiquitin ligases
The SCF and APC/C E3 ligases are both members of the Cullin-RING ligase (CRL) superfamily. Cul1 and Apc2 (light grey) are the scaffold proteins of SCF and APC/C, respectively. On one end, they bind to a RING finger protein, Rbx1 or Apc11 (dark grey), which recruits the E2 ubiquitin conjugating enzyme (UBC). On their other end, they connect to the substrate specific unit via an adaptor molecule (red). In the case of SCF, the F-box proteins are the variable substrate binding components (orange), while Cdh1 and Cdc20 (in somatic cells), together with Apc10, recruit substrates to the APC/C. The scheme illustrates the relationship between APC/C and SCF components and does not represent the topology of APC/C subunits.
Figure 2
Figure 2. SCF and APC/C mediated degradation processes in G1 phase and the response to mitogen stimulation
A. APC/CCdh1 maintains a stable G1 phase by targeting mitotic proteins like Aurora A, Aurora B, Plk1, cyclin A, and cyclin B for degradation. In addition, APC/CCdh1 prevents premature accumulation of positive cell cycle regulators, such as Ets2, Cdc6, and Cdc25A. The CDK inhibitors p21 and p27 are stabilized via APC/CCdh1-dependent degradation of Skp2 to keep CDK activity low during G1. B. Upon mitogen stimulation, SCFβTrCP mediates the degradation of inhibitory or proapoptotic proteins, such as PCDC4, DEPTOR, and BimEL, promoting cell growth. Upon mitogen withdrawal, SCFFbxo9 targets Tel2 and Tti1 for degradation within mTORC1 to attenuate mTORC1 activity and sustain mTORC2 signaling. C. At the G1/S transition, APC/CCdh1 activity is inhibited through several mechanisms, such as inhibitory phosphorylation by CDKs and binding to Emi1. Skp2-dependent degradation of p21 and p27 leads to activation of cyclin E-Cdk2, which initiates S phase before being degraded via SCFFbw7. See main text for more details.
Figure 3
Figure 3. SCF and APC/C mediated degradation processes in S and G2 phases of the cell cycle
A. In early G2, APC/CCdh1 remains inactivated, SCFSkp2 maintains cyclin A-Cdk1/2 activity via degradation of p21 and p27, SCFFbw7 promotes cyclin E degradation, and SCFNIPA prevents premature accumulation of nuclear cyclin B. Other S phase proteins (e.g., RRM2 and CP110) are also degraded via cyclin F to stop dNTP production and assure centrosomes are only replicated once per cell cycle. B. At the G2/M transition, SCFSkp2 continues to target p21 and p27, while Wee1 is degraded in a Plk1- and SCFβTrCP-dependent manner to release cyclin B-Cdk1 from inhibition. See main text for more details.
Figure 4
Figure 4. Role of SCF and APC/C ligases in the response to DNA damage
Upon DNA damage, SCF and APC/C activate S and G2 checkpoints to halt cell cycle progression. Chk1 (which is activated by ATR) promotes the SCFβTrCP-dependent of Cdc25A to inhibit CDK activity, while dephosphorylation of Cdh1 by Cdc14B allows for Plk1 degradation and subsequent stabilization of Claspin and Wee1. See main text for more details.
Figure 5
Figure 5. SCF and APC/C mediated degradation processes during mitosis
A. In early mitotis, SCFβTrCP ubiquitylates Emi1 to eliminate the repression of APC/CCdh1 (which remains inactive because of Cdh1 phosphorylation by CDKs) and, possibly, APC/CCdc20. However, during activation of the Spindle Assembly Checkpoint (SAC), APC/CCdc20 activity is repressed, with cyclin B-Cdk1 contributing to its inhibition. B. After fulfillment of the SAC, APC/CCdc20 inhibition is relieved, allowing it to target mitotic cyclins and Securin for degradation, the latter leading to Separase activation and sister chromatid separation. With mitotic progression, APC/CCdc20 activity decreases via several mechanisms, and APC/CCdh1 assembles to target cell cycle proteins for degradation. See main text for more details.

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