The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention

Abstract

Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptionl co-regulator. The overexpression of cyclin D1 has been linked to the development and progression of cancer. Deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. Recent findings have identified novel mechanisms involved in the regulation of cyclin D1 stability. A number of therapeutic agents have been shown to induce cyclin D1 degradation. The therapeutic ablation of cyclin D1 may be useful for the prevention and treatment of cancer. In this review, current knowledge on the regulation of cyclin D1 degradation is discussed. Novel insights into cyclin D1 degradation are also discussed in the context of ablative therapy. A number of unresolved questions regarding the regulation of cellular cyclin D1 levels are also addressed.

Figure 1

Schematic representation of cyclin D1 (top) and cyclin D1b (bottom) regulatory sequences. Cyclin D1 stability is regulated by various mechanisms. The n-terminal region has recently been shown to be important for regulating stability [27]. (?) The mechanisms that regulate cyclin D1 stability via the n-terminal remain to be clearly defined. The RxxL motif is required for APC (Anaphase Promoting Complex) mediated degradation following genotoxic insult [48]. GSK3β phosphorylates threonine residue 286 (T286) and regulates cyclin D1 nuclear export and stability [5, 40]. p38^SAPK2 and ERK2 have also been shown to regulate cyclin D1 stability by phosphorylating T286 [9, 49, 114]. The threonine 288 residue (T288) has also been shown to regulate cyclin D1 stability. Phosphorylation of T288 is mediated by the mirk/Dyrk 1b kinase [47]. In cyclin D1b, regulatory motifs and residues within the c-terminal region downstream of residue 240 are replaced by sequence from intron 4 of the CCND1 gene [62, 63]. Adapted from Knudsen, 2006 [13, 65].

Figure 2

Regulation of cyclin D1 degradation. A. Cyclin D1 does not contain a nuclear localization signal (NLS) [159] and its sequestration may result in accumulation within the cytoplasm [45, 75, 76]. B. Cytoplasmic cyclin D1 is transported into the nucleus in association with its binding partners e.g CDK4 and possibly various transcription factors (TF) [159-161]. C. p38^SAPK2 has been shown to phosphorylate cyclin D1 on threonine residue 286 (T286) and induce its proteasomal degradation [49, 114]. It is unclear if the F-box proteins FBX4 and FBXW8 are involved in mediating p38^SAPK2 induced cyclin D1 degradation in the cytoplasm. D, E. Within the nucleus, active cyclin dependent kinase 4 (CDK4) or CDK6- cyclin D1 complexes phosphorylate the retinoblastoma protein (RB) [2]. Cyclin D1 can also influence the activity of various transcription factors independently of CDK4/6 [4]. F. Free cyclin D1 is degraded through the ubiquitin dependent 26S proteasomal degradation pathway independently of glycogen synthase kinase 3β (GSK3β) [46]. Antizyme can also mediate cyclin D1 degradation via the 26S proteasome independently of ubiquitin [56]. G, H. GSK3β phosphorylates cyclin D1 on T286 which facilitates its nuclear export by the exportin CRM1. GSK3β influences cyclin D1 stability since the phosphorylated form of the cyclin is subsequently degraded within the cytoplasm [5, 6, 40]. I. Phosphorylation of T288 is mediated by the mirk/Dyrk 1b kinase and can induce cyclin D1 degradation [47]. J. FBX4 and FBXW8 ubiquitylate phosphorylated cyclin D1 within the cytoplasm, targeting it for 26S proteasomal degradation [8, 9].