Protein Degradation in Cell Cycle

Shavali Shaik, Harvard Medical School, Boston, Massachusetts, USA
Pengda Liu, Harvard Medical School, Boston, Massachusetts, USA
Hidefumi Fukushima, Harvard Medical School, Boston, Massachusetts, USA
Zhiwei Wang, Harvard Medical School, Boston, Massachusetts, USA
Wenyi Wei, Harvard Medical School, Boston, Massachusetts, USA

Published online: June 2012

DOI: 10.1002/9780470015902.a0023158

Cell cycle is a series of events that take place within a cell, leading to its division and duplication. Protein degradation through ubiquitin‐mediated proteolysis plays an important role in the cell‐cycle regulation. Most importantly, the Anaphase Promoting Complex/Cyclosome (APC/C) and the Skp1‐Cullin‐1‐F‐box complex (SCF) are the two major E3 ubiquitin ligase complexes that regulate proper cell cycle transitions by timely degrading the various key cell cycle regulators. The SCF complex controls the G1/S and the G2/M transitions by degrading Cyclin D, Cyclin E, p27, CDC6 and Wee1, whereas the APC complex facilitates the transition from metaphase to anaphase by degrading Cyclin A, Cyclin B, Securin and many other substrates. The APC complex also plays an integral role in the maintenance of chromatin metabolism, particularly in G1 and G0 via destruction of the aurora A kinase. These cell cycle transitions are tightly regulated, and defective regulation of cell cycle leads to genomic instability and ultimately cancer development.

Key Concepts:

  • Cell cycle is an essential physiological process, which generates additional number of cells when the body needs them.
  • Cell cycle checkpoints are the built‐in control mechanisms that ensure the accuracy of cell division in eukaryotic cells.
  • The timely destruction of various cell cycle regulators by the APC/C and the SCF complexes is necessary for proper cell cycle progression.
  • The protein degradation pathways involve the ubiquitin‐mediated modification of substrates, which are subsequently targeted for degradation by the 26S proteasome.
  • Misregulation of the cell cycle processes leads to abnormal cell division, chromosomal instability and subsequently cancer development.

Keywords: ubiquitination; E3 ubiquitin ligase; cell cycle; protein degradation; proteasome; APC; SCF

Figure 1. Cell cycle regulation by the APC/C and the SCF E3 ubiquitin ligase complexes. SCF ubiquitinates substrates from the late G1 to the early M phase, whereas the APC/C is active from the mid‐M phase (anaphase) to the end of G1 phase. SCF complex controls the G1/S and the G2/M transitions by degrading Cyclin D, Cyclin E, p27, CDC6 and wee1, whereas the APC complex facilitates the transition from metaphase to anaphase by degrading Cyclin A, Cyclin B and Securin, as well as many other APC substrates.
Figure 2. Illustrated mechanism of protein degradation via the ubiquitin‐proteasome pathway. The ubiquitin molecule is activated by the E1 enzyme (ubiquitin activating enzyme). The E2 enzyme, also known as the Ub‐conjugating enzyme, once conjugated to activated ubiquitin, binds one of several ubiquitin ligases (E3) via a structurally conserved binding region. The E3 enzyme, which functions in concert with E2 enzyme, transfers the ubiquitin from the E2 to the substrate proteins. The E3 enzyme determines the substrate specificity of the 3step ubiquitination process. The ubiquitinated substrate protein is ultimately degraded in the 26S proteasome.
Figure 3. Defects in protein degradation caused by dysfunction of E3 ligases leads to abnormal cell cycle progression and ultimately cancer development. (a) SCFFbw7 degrades the Cyclin E, Myc, Mcl‐1, Jun and Notch oncoproteins. Mutations or dysfunction of Fbw7 leads to stabilisation of cyclinE, c‐Myc and Mcl‐1 that leads to development of various cancers. (b) SCFskp2 degrades the p21, p27 and FOXO1 tumour suppressor proteins. Overexpression of Skp2 is frequently observed in several human cancers including lymphoma, breast and prostate cancer. (c) SCFβ−TRCP degrades key proteins including Ikk, β‐Catenin and REST. In many cancers, β‐TRCP is overexpressed and contributes to increased degradation of Ikk which leads to hyperactivation of NFkB pathway that potentially involved in tumourigenesis. However, in very rare cases, β‐TRCP behaves as a tumour suppressor and deletion or loss of function of β‐TRCP leads to stabilisation of β‐Catenin that contributes to tumourigenesis. (d) On the other hand, APCCdh1 controls the degradation of various cell cycle regulators including Skp2, Cyclin A, Cyclin B, Aurora B, PLK1, Securin and Geminin, most of which function as oncoproteins in vivo. Dysfunction of Cdh1 related to the development of breast, colon, gastric and cervical cancers, and deletion of Cdh1 in mouse predisposes the mice to tumour development.
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Related Sub-Topics:

Cell Biology of Cancer | Cell Cycle | Protein Folding, Evolution and Degradation | Protein Degradation
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Article Title: Protein Degradation in Cell Cycle
 
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Shaik, Shavali, Liu, Pengda, Fukushima, Hidefumi, Wang, Zhiwei, and Wei, Wenyi(Jun 2012) Protein Degradation in Cell Cycle. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023158]