Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation

Kim, Ji Hyun; Ki, Soo Mi; Joung, Je-Gun; Scott, Eric; Heynen‐Genel, Susanne; Aza-Blanc, Pedro; Kwon, Chil Hun; Kim, Joon; Gleeson, Joseph G.; Lee, Ji Eun

doi:10.1016/j.bbamcr.2016.03.021

Cited by 26 publications

(29 citation statements)

References 44 publications

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“…These findings are in line with previous observations linking cilioproteins to regulation of proteasomal activity, centrosome composition and mRNA processing 39–41 .…”

Section: Discussionsupporting

confidence: 93%

The centrosomal OFD1 protein interacts with the translation machinery and regulates the synthesis of specific targets

Iaconis

Monti

Renda

et al. 2017

Sci Rep

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Protein synthesis is traditionally associated with specific cytoplasmic compartments. We now show that OFD1, a centrosomal/basal body protein, interacts with components of the Preinitiation complex of translation (PIC) and of the eukaryotic Initiation Factor (eIF)4F complex and modulates the translation of specific mRNA targets in the kidney. We demonstrate that OFD1 cooperates with the mRNA binding protein Bicc1 to functionally control the protein synthesis machinery at the centrosome where also the PIC and eIF4F components were shown to localize in mammalian cells. Interestingly, Ofd1 and Bicc1 are both involved in renal cystogenesis and selected targets were shown to accumulate in two models of inherited renal cystic disease. Our results suggest a possible role for the centrosome as a specialized station to modulate translation for specific functions of the nearby ciliary structures and may provide functional clues for the understanding of renal cystic disease.

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“…These findings are in line with previous observations linking cilioproteins to regulation of proteasomal activity, centrosome composition and mRNA processing 39–41 .…”

Section: Discussionsupporting

confidence: 93%

The centrosomal OFD1 protein interacts with the translation machinery and regulates the synthesis of specific targets

Iaconis

Monti

Renda

et al. 2017

Sci Rep

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“…We analyzed a set of resources including public databases reporting results from functional small interfering RNA screens to identify regulators of ciliogenesis (18, 19), a database of genes linked to morbid ciliopathies (20), and additional resources reporting genes linked to ciliary dynamics (18, 21, 22). We evaluated the intersection of genes noted in these resources with genes that had been defined as HSP90 targets or that were regulated by HSP90 inhibition (23–25, 35) (Supplemental Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…Data were assembled from public databases reporting RNA interference–defined regulators of ciliogenesis (18, 19), genes linked to morbid ciliopathies (20), and a compendium of genes linked to ciliary dynamics and function (21, 22). HSP90 interactors were retrieved using the metasearch engines Ingenuity Pathway Analysis (Qiagen, Germantown, MD, USA; http://www.qiagen.com/ingenuity) and String (http://string.embl.de/) (23), and from the HSP90 interaction database HSP90Int.…”

Section: Methodsmentioning

confidence: 99%

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

et al. 2018

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Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance. We determined that ganetespib, a clinical HSP90 inhibitor, inhibited proteasomal repression of NEK8 and the Aurora-A activator trichoplein, rapidly activating Aurora-A kinase and causing ciliary loss in vitro. Using conditional mouse models for ADPKD, we performed long-term (10 or 50 wk) dosing experiments that demonstrated HSP90 inhibition caused durable in vivo loss of cilia, controlled cystic growth, and ameliorated symptoms induced by loss of Pkd1 or Pkd2. Ganetespib efficacy was not increased by combination with 2-deoxy-d-glucose, a glycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.-Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korobeynikov, V., Gaponova, A., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger-Nukpezah, T. N., Somlo, S., Proia, D. A., Golemis, E. A. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD).

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“…This study may suggest that (de)ciliation is regulated by protein synthesis and destruction coordinated with cell cycle [76]. Several excellent reviews have described the importance of timely protein synthesis or destruction in ciliogenesis or deciliation, respectively [14–20].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of ciliogenesis suppression in dividing cells

Goto

Inaba

Inagaki

2016

Cell. Mol. Life Sci.

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The primary cilium is a non-motile and microtubule-enriched protrusion ensheathed by plasma membrane. Primary cilia function as mechano/chemosensors and signaling hubs and their disorders predispose to a wide spectrum of human diseases. Most types of cells assemble their primary cilia in response to cellular quiescence, whereas they start to retract the primary cilia upon cell-cycle reentry. The retardation of ciliary resorption process has been shown to delay cell-cycle progression to the S or M phase after cell-cycle reentry. Apart from this conventional concept of ciliary disassembly linked to cell-cycle reentry, recent studies have led to a novel concept, suggesting that cells can suppress primary cilia assembly during cell proliferation. Accumulating evidence has also demonstrated the importance of Aurora-A (a protein originally identified as one of mitotic kinases) not only in ciliary resorption after cell-cycle reentry but also in the suppression of ciliogenesis in proliferating cells, whereas Aurora-A activators are clearly distinct in both phenomena. Here, we summarize the current knowledge of how cycling cells suppress ciliogenesis and compare it with mechanisms underlying ciliary resorption after cell-cycle reentry. We also discuss a reciprocal relationship between primary cilia and cell proliferation.

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Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation

Cited by 26 publications

References 44 publications

The centrosomal OFD1 protein interacts with the translation machinery and regulates the synthesis of specific targets

The centrosomal OFD1 protein interacts with the translation machinery and regulates the synthesis of specific targets

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

Mechanisms of ciliogenesis suppression in dividing cells

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