The intraflagellar transport component IFT88/polaris is a centrosomal protein regulating G1-S transition in non-ciliated cells

Abstract

Loss of normal primary cilia function in mammals is linked to proliferative diseases, such as polycystic kidney disease, suggesting a regulatory relationship between cilia and cell cycle. The primary cilium expressed by most mammalian cells is nucleated from the elder centriole of the centrosome. The relationship between centrosome and cilia suggests that these structures share functions and components. We now show that IFT88/polaris, a component of the intraflagellar transport, remains associated to the centrosome in a proliferative state. IFT88/polaris is tightly associated with the centrosome throughout the cell cycle in a microtubule- and dynein-independent manner. IFT88/polaris tetratricopeptide repeat motifs are essential for this localization. Overexpression of IFT88/polaris prevents G1-S transition and induces apoptotic cell death. By contrast, IFT88/polaris depletion induced by RNA interference promotes cell-cycle progression to S, G2, and M phases. Finally, we demonstrate that IFT88/polaris interacts with Che-1, an Rb-binding protein that inhibits the Rb growth suppressing function. We propose that IFT88/polaris, a protein essential for ciliogenesis, is also crucial for G1-S transition in non-ciliated cells.

Centrosomal Protein DZIP1 Regulates Hedgehog Signaling by Promoting Cytoplasmic Retention of Transcription Factor GLI3 and Affecting Ciliogenesis

“…The cells were then immunostained for FLAG-DZIP1 and IFT88, an IFT component that localizes to the basal bodies and accumulates in the tips of the primary cilia in quiescent cells (32). As expected, the DZIP1 full-length protein, DZIP1FL, was enriched in the base of the cilia and colocalized with IFT88 at the basal body in addition to its diffuse localization in the cytoplasm (Fig.…”

Cilia and cell cycle re-entry

“…76,78 Depletion of IFT88 in HeLa cells promoted G 1 /S progression, while overexpression of IFT88 led to a G 1 arrest and induced apoptosis. 76 Recently, Doxsey and colleagues reported a new role of IFT88 in maintaining proper spindle orientation during cell division through the regulation of the astral microtubules. 77 Depletion of IFT88 in HeLa cells and zebrafish embryos as well as kidney cells derived from Ift88 +/-mice all showed mitotic misorientation and a delay in mitotic progression.…”

“…76,77 In HeLa cells, which lack cilia, IFT88 was shown to regulate G 1 /S transition through a physical interaction with Che-1, an inhibitor of the DNA damage checkpoint protein, retinoblastoma. 76,78 Depletion of IFT88 in HeLa cells promoted G 1 /S progression, while overexpression of IFT88 led to a G 1 arrest and induced apoptosis. 76 Recently, Doxsey and colleagues reported a new role of IFT88 in maintaining proper spindle orientation during cell division through the regulation of the astral microtubules.…”

Cilia, adenomatous polyposis coli and associated diseases

“…The relationship between primary cilia and cell-cycle control is clearly demonstrated by the mutation of IFT genes. In HeLa cell, RNA interference technique is used to inhibit IFT88 gene and the cell cycle is promoted, while the overexpression of IFT88 would delay the transformation from G1 to S phase (Robert et al, 2007).…”