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Figure 2 | Molecular Cancer

Figure 2

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

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. p38SAPK2 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 p38SAPK2 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].

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