Protein Degradation in Cell Cycle

Abstract

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.

Dynamics of protein synthesis and degradation through the cell cycle

“…While the regulation of transcriptional and translational efficiency throughout the cell cycle is relatively well studied on a global and transcript-specific level, our knowledge about cell cycle dependent changes in protein degradation has long been limited to very specific cases such as cyclins and other key cell cycle regulatory proteins [62] .…”

Single Live Cell Monitoring of Protein Turnover Reveals Intercellular Variability and Cell-Cycle Dependence of Degradation Rates

“…Larger changes in protein synthesis occur in M phase, during which transcriptional activity (Palozola et al, 2017;Parsons and Spencer, 1997) and transla-tional efficiency of most mRNAs are strongly reduced (Tanenbaum et al, 2015). In contrast, our understanding on changes in protein degradation rates over the cell cycle is restricted to specific cases such as proteins involved in cell-cycle regulation (Shaik et al, 2012) and targets of the GSK3 kinase (Acebron et al, 2014). Furthermore, most of these studies are limited by low temporal resolution, the use of cell-cycle synchronizing drugs that can interfere with translation (Coldwell et al, 2013), and cell population-based measurements that obscure cell-tocell variability.…”

SCFβ-TRCP targets MTSS1 for ubiquitination-mediated destruction to regulate cancer cell proliferation and migration

“…The ubiquitin proteasome system (UPS) plays an important role in the timely regulation of key cellular proteins and thereby controlling many cellular processes including cell signaling and cell cycle regulation [19]. Dysfunction of the UPS is involved in the development of many diseases including cancer [20, 21].…”

“…Dysfunction of the UPS is involved in the development of many diseases including cancer [20, 21]. Three enzymes are involved in protein ubiquitination and destruction process, the ubiquitin-activating enzyme (E1), the ubiquitin-conjugating enzyme (E2) and the ubiquitin ligase (E3), respectively and the E3 ligases determine the substrate specificity of the three-step ubiquitination process [19]. The SCF β-TRCP E3 ubiquitin ligase complex plays a key role in cell cycle regulation [19].…”

“…Three enzymes are involved in protein ubiquitination and destruction process, the ubiquitin-activating enzyme (E1), the ubiquitin-conjugating enzyme (E2) and the ubiquitin ligase (E3), respectively and the E3 ligases determine the substrate specificity of the three-step ubiquitination process [19]. The SCF β-TRCP E3 ubiquitin ligase complex plays a key role in cell cycle regulation [19]. However, its exact role as a tumor suppressor or oncogene might be tissue- or cellular context-dependent as both loss of β-TRCP, and aberrant upregulation of β-TRCP, have been reported in different types of human cancers [22].…”