D-Type Cyclins in Development and Disease

Abstract

D-type cyclins encode G1/S cell cycle checkpoint proteins, which play a crucial role in defining cell cycle exit and progression. Precise control of cell cycle exit is vital during embryonic development, with defects in the pathways regulating intracellular D-type cyclins resulting in abnormal initiation of stem cell differentiation in a variety of different organ systems. Furthermore, stabilisation of D-type cyclins is observed in a wide range of disorders characterized by cellular over-proliferation, including cancers and overgrowth disorders. In this review, we will summarize and compare the roles played by each D-type cyclin during development and provide examples of how their intracellular dysregulation can be an underlying cause of disease.

Keywords: CDK4; cancer; cell cycle; cyclin D1; cyclin D2; cyclin D3; overgrowth; proliferation.

Figure 1

The regulation of Cyclin D: Cyclin D is expressed in response to mitogenic stimulation through the Ras (in light blue) and PI3K-Akt (in light green) pathways, which stimulate the synthesis and promote the stability of cyclin D, respectively. CDK-interacting proteins/kinase inhibitory proteins (CIP/KIP) such as p21 and p27 stabilize and facilitate the formation of the cyclin D-CDK4/6 complex. In the nucleus, the activity of this complex is terminated by the phosphorylation of C-terminal threonine by GSK3ß or, potentially, other unknown kinases. Once phosphorylated, cyclin D is then polyubiquitylated by the CRL4^AMBRA1 E3 ubiquitin ligase and is then subsequently degraded.

Figure 2

Comparison of cyclins D1, D2, and D3. The three D-type cyclins share a number of conserved sequences and domains. The Rb-binding domain, located at the N-terminus, is responsible for binding the C-terminal helix of Rb when cyclin D is bound to CDK4/6. The cyclin box domain is a heavily conserved region of ~100 amino acids located in the N-terminus of each D-cyclin, which facilitates binding to CDK4/6. Mutagenesis of Lys112 (CCND1 and CCND3) and Lys111 (CCND2), in particular, abolishes binding to CDK4, demonstrating the residue’s essential role in mediating CDK-binding. The PEST sequence located at the C-terminus is required to mediate the degradation of cyclin D. Mutations at the Threonine phosphodegron site induce the stabilisation of cyclin D, resulting in increased progression of the cell cycle into the S-phase and genomic instability. CCND1 also possess an LxxLL motif, which mediates ligand-dependent interaction with nuclear receptors such as Erα.