Cyclin D degradation by E3 ligases in cancer progression and treatment

Abstract

D cyclins include three isoforms: D1, D2, and D3. D cyclins heterodimerize with cyclin-dependent kinase 4/6 (CDK4/6) to form kinase complexes that can phosphorylate and inactivate Rb. Inactivation of Rb triggers the activation of E2F transcription factors, which in turn regulate the expression of genes whose products drive cell cycle progression. Because D-type cyclins function as mitogenic sensors that link growth factor signaling directly with G₁ phase progression, it is not surprising that D cyclin accumulation is dysregulated in a variety of human tumors. Elevated expression of D cyclins results from gene amplification, increased gene transcription and protein translation, decreased microRNA levels, and inefficiency or loss of ubiquitylation-mediated protein degradation. This review focuses on the clinicopathological importance of D cyclins, how dysregulation of Ubiquitin-Proteasome System (UPS) contributes to the overexpression of D cyclins, and the therapeutic potential through targeting D cyclin-related machinery in human tumors.

Keywords: Cancer; D cyclin; E3 ubiquitin ligase; Protein degradation.

Figure 1. Schematic illustration of cell cycle regulation.

Cell cycle is divided into four phases: G₁ (gap phase 1), S (DNA synthesis), G₂ (gap phase 2), and M (mitosis). Cell cycle progression is regulated by cyclins and their cognate CDKs. As the important regulator of G₁ phase, CDK4/6 inhibitors have been developed, for example, PD-0332991 (palbociclib), LY2835219 (abemaciclib), and LEE011 (ribociclib) that are approved by U.S. Food and Drug Administration to treat human tumors.

Figure 2. Ubiquitylation-medicated protein degradation.

Protein ubiquitylation is catalyzed by the concerted and coordinated action of three enzymes: E1, ubiquitin-activating enzyme that produces an active ubiquitin using energy to generate a thioester linkage between itself and ubiquitin molecule; E2, ubiquitin-conjugating enzyme that is both an ubiquitin receptor for E1 and an ubiquitin donor for substrates or E3s; E3, ubiquitin ligase that binds to E2s and its substrates to assist ubiquitin transfer from E2s to substrates or directly recognizes and conjugates ubiquitin to its targets. Polyubiquitylated proteins will be degraded in proteasome, a complex intracellular structure composed of multiple enzymatic complexes.

Figure 3. Illustration of phosphorylation sites of D cyclins.

As for phosphorylation-mediated degradation, the conserved sites for Thr286 in cyclin D1 are Thr280 in cyclin D2 and Thr283 in cyclin D3, respectively.