Current topics of functional links between primary cilia and cell cycle

Abstract

Primary cilia, microtubule-based sensory structures, orchestrate various critical signals during development and tissue homeostasis. In view of the rising interest into the reciprocal link between ciliogenesis and cell cycle, we discuss here several recent advances to understand the molecular link between the individual step of ciliogenesis and cell cycle control. At the onset of ciliogenesis (the transition from centrosome to basal body), distal appendage proteins have been established as components indispensable for the docking of vesicles at the mother centriole. In the initial step of axonemal extension, CP110, Ofd1, and trichoplein, key negative regulators of ciliogenesis, are found to be removed by a kinase-dependent mechanism, autophagy, and ubiquitin-proteasome system, respectively. Of note, their disposal functions as a restriction point to decide that the axonemal nucleation and extension begin. In the elongation step, Nde1, a negative regulator of ciliary length, is revealed to be ubiquitylated and degraded by CDK5-SCF(Fbw7) in a cell cycle-dependent manner. With regard to ciliary length control, it has been uncovered in flagellar shortening of Chlamydomonas that cilia itself transmit a ciliary length signal to cytoplasm. At the ciliary resorption step upon cell cycle re-entry, cilia are found to be disassembled not only by Aurora A-HDAC6 pathway but also by Nek2-Kif24 and Plk1-Kif2A pathways through their microtubule-depolymerizing activity. On the other hand, it is becoming evident that the presence of primary cilia itself functions as a structural checkpoint for cell cycle re-entry. These data suggest that ciliogenesis and cell cycle intimately link each other, and further elucidation of these mechanisms will contribute to understanding the pathology of cilia-related disease including cancer and discovering targets of therapeutic interventions.

Keywords: Cancer; Cell cycle; Ciliogenesis; Primary cilia; Ubiquitin–proteasome system.

Fig. 1

Ciliogenesis cycle and cell cycle. Multiple steps (a–f) of primary cilia formation in ciliogenesis cycle are shown in related to cell cycle

Fig. 2

Molecular mechanisms linking ciliogenesis and cell cycle regulation. Recent findings to uncover the molecular link between the individual step (a–g) of ciliogenesis and cell cycle are depicted. Red letters indicate kinases and blue letters indicate molecules related to ubiquitin–proteasome pathway or autophagy

Fig. 3

Involvement of the ubiquitin–proteasome system in ciliogenesis and cell cycle control. Ciliogenesis is regulated by the ubiquitin–proteasome system in a cell cycle-dependent manner

Fig. 4

A model for cilia length and cell cycle. Molecular mechanisms of flagellar shortening of Chlamydomonas and primary cilia resorption in mammalian cells are shown (upper portion). In addition, a possible link between ciliary length signal and cell cycle is depicted (lower portion)

Fig. 5

Effects of trichoplein depletion on cell cycle regulators. Proliferating RPE1 cells were transfected with siRNA for control or trichoplein (#1 and #2), and then cultured for 72 h. The cell extracts were subjected to immunoblotting analysis with p27^Kip1, p53, p21^Cip1, p16^INK4a, trichoplein, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). As controls of immunoblotting with p27^Kip1 or p53/p21^Cip1, RPE1 cells were subjected to 72 h serum starvation or UV irradiation (10 J/m², 24 h), respectively. These are original data for this review