The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression

Abstract

The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell-cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), the activities of which are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors (CKIs). Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell-cycle process via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor proteins and oncoproteins or, inversely, abnormally high accumulation results in cell proliferation deregulation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the UPS machinery regulation of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell-cycle transition, cancer treatment, and the development of anti-cancer drugs.

Keywords: CDKs; CKIs; DUBs; E3 ubiquitin ligases; UPS; cell-cycle regulation; cyclins.

Figure 1

A brief overview of the cell cycle. The normal cell cycle consists of four phases: Gap 1 (G1), DNA synthesis (S), Gap 2 (G2), and mitosis (M). Most nondividing cells exit from the cell cycle and go into quiescent state (G0) but also can re-enter the cell cycle under appropriate stimulation. A cell is committed to entering the cell cycle after passing the restriction point (R). Each phase in cell cycle progression is driven by the activities of cyclin–CDK complexes.

Figure 2

Overview of the ubiquitin-proteasome system. Ubiquitination is a multistep enzyme cascade. The first step is that free ubiquitin (Ub) is activated by an E1 ubiquitin-activating enzyme in an ATP-dependent manner. Then, the activated ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme and is attached to a substrate protein through the actions of an E3 ubiquitin-ligase enzyme, which identified substrate specifically. Finally, the ubiquitinated substrate protein is subsequently recognized by the 26S proteasome and degraded into small peptides and amino acids. Deubiquitinating enzymes (DUBs) reverse the ubiquitination process through removing polyubiquitin chains from proteins to maintain intracellular ubiquitin levels.

Figure 3

E3 ubiquitin ligases and DUBs regulate cell cycle by targeting cyclins and CDKs. E3 ubiquitin ligases (red ovals) trigger the ubiquitylation and proteolysis of cyclins and CDKs at specific stages of the cell cycle. Most deubiquitinating enzymes (green ovals) deubiquitinates and stabilizes cyclins and CDKs, promoting cell cycle progression. However, OTUD6B is likely to participate in the downregulation of cyclin D2 through an intermediate, but the mechanism is not yet clear. UCH-L1 does not control the cell cycle by stabilizing substrate proteins, but physically interacts with CDK1, CDK4, and CDK5 and enhances CDKs activity. Refer to the main text for details.

Figure 4

Summary of E3 ubiquitin ligases involved in the regulation of CKIs. Summary of E3 ligases that regulate cell cycle progression by targeting p21, p27, p57, or p16. p21, p27, and p57 are all controlled by SCF^SKP2. Currently, the identification of the E3 ligase of the INK4 protein family is still insufficient.