Cell Cycle–Dependent Ciliogenesis and Cancer

Plotnikova, Olga; Golemis, Erica A.; Pugacheva, Elena N.

doi:10.1158/0008-5472.can-07-5838

Cited by 153 publications

(150 citation statements)

References 40 publications

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“…NEDD9 (also known as HEF1 and Cas-L) is a scaffold for cell signaling interactions that govern cell attachment and migration (4, 5), survival (6), mitogenic signaling and cell cycle control (7)(8)(9)(10), and ciliary resorption (11,12). To date, NEDD9 has been most studied in the context of cancer, because deregulated expression of NEDD9 accompanies and promotes metastasis in a large and growing number of cancer types, whereas genetic ablation of NEDD9 has a significant modifier function for tumor initiation and progression (8,13,14).…”

Section: Hef1 | Ganetespib | Sta-2842mentioning

confidence: 99%

Nedd9 restrains renal cystogenesis in Pkd1 ^−/− mice

Nikonova

Plotnikova

Serzhanova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance This study uses mouse models for the first time to our knowledge to identify that NEDD9, a nonenzymatic scaffolding protein that is commonly amplified in cancer, has an important restraining function for the development of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). In the absence of NEDD9, failure to activate Aurora-A kinase causes multiple abnormalities in cilia, intensifying the effect of genetic deficiency of mutations in the polycystic kidney disease (PKD) 1 gene, the most common cause of PKD. As important implications, clinical inhibitors of Aurora-A also intensified ADPKD induced by mutation of PKD1 , suggesting caution in use of these agents, whereas recently reported polymorphisms in Nedd9 may contribute to the genetic heterogeneity of ADPKD presentation in affected families.

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Section: Hef1 | Ganetespib | Sta-2842mentioning

confidence: 99%

Nedd9 restrains renal cystogenesis in Pkd1 ^−/− mice

Nikonova

Plotnikova

Serzhanova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…As CYLD is a tumour suppressor, and primary cilia usually form in the G0/G1 phase of the cell cycle 28 , we also wanted to determine whether both cell types were able to undergo cell cycle arrest on serum starvation. Again, after FACS analysis and KI67…”

Section: Cyld Interacts With Cap350 At the Centrosome/basal Bodiesmentioning

confidence: 99%

The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

et al. 2014

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CYLD is a tumour suppressor gene mutated in familial cylindromatosis, a genetic disorder leading to the development of skin appendage tumours. It encodes a deubiquitinating enzyme that removes Lys63-or linear-linked ubiquitin chains. CYLD was shown to regulate cell proliferation, cell survival and inflammatory responses, through various signalling pathways. Here we show that CYLD localizes at centrosomes and basal bodies via interaction with the centrosomal protein CAP350 and demonstrate that CYLD must be both at the centrosome and catalytically active to promote ciliogenesis independently of NF-kB. In transgenic mice engineered to mimic the smallest truncation found in cylindromatosis patients, CYLD interaction with CAP350 is lost disrupting CYLD centrosome localization, which results in cilia formation defects due to impairment of basal body migration and docking. These results point to an undiscovered regulation of ciliogenesis by Lys63 ubiquitination and provide new perspectives regarding CYLD function that should be considered in the context of cylindromatosis.

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“…In addition, several proliferating cells were found to have primary cilia. Knowing that the cell turnover is increased in the proliferating zone and that primary cilia are absent in replicating cells, 10 it is possible that only a subset of proliferating cells are in mitosis. This suggests that the cilia length is directly related to cell cycle duration.…”

Section: Cilia In Growth Plate and Osteochondroma Ce De Andrea Et Almentioning

confidence: 99%

“…Retrograde transport, from the tip to the base of the cilium, is mediated by dynein 1B. 10 The link between cilia function and growth plate development is described in several recent studies. Primary cilia have been implicated as recipients of some signaling pathways essential for the regulation of the growth plate, such as the non-canonical Wnt and Indian Hedgehog pathways.…”

mentioning

confidence: 99%

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

Andrea

Wiweger

Prins

et al. 2010

Laboratory Investigation

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Primary cilia are specialized cell surface projections found on most cell types. Involved in several signaling pathways, primary cilia have been reported to modulate cell and tissue organization. Although they have been implicated in regulating cartilage and bone growth, little is known about the organization of primary cilia in the growth plate cartilage and osteochondroma. Osteochondromas are bone tumors formed along the growth plate, and they are caused by mutations in EXT1 or EXT2 genes. In this study, we show the organization of primary cilia within and between the zones of the growth plate and osteochondroma. Using confocal and electron microscopy, we found that in both tissues, primary cilia have a similar formation but a distinct organization. The shortest ciliary length is associated with the proliferative state of the cells, as confirmed by Ki-67 immunostaining. Primary cilia organization in the growth plate showed that nonpolarized chondrocytes (resting zone) are becoming polarized (proliferating and hypertrophic zones), orienting the primary cilia parallel to the longitudinal axis of the bone. The alignment of primary cilia forms one virtual axis that crosses the center of the columns of chondrocytes reflecting the polarity axis of the growth plate. We also show that primary cilia in osteochondromas are found randomly located on the cell surface. Strikingly, the growth plate-like polarity was retained in sub-populations of osteochondroma cells that were organized into small columns. Based on this, we propose the existence of a mixture ('mosaic') of normal lining (EXT þ /À or EXT wt/wt ) and EXT À/À cells in the cartilaginous cap of osteochondromas.

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Cell Cycle–Dependent Ciliogenesis and Cancer

Abstract: In mammals, most cell types have primary cilia, protruding structures involved in sensing mechanical and chemical signals from the extracellular environment that act as major communication hubs for signaling controlling cell differentiation and polarity.

Cited by 153 publications

References 40 publications

Nedd9 restrains renal cystogenesis in Pkd1 ^−/− mice

Nedd9 restrains renal cystogenesis in Pkd1 ^−/− mice

The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

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Cell Cycle–Dependent Ciliogenesis and Cancer

Abstract: In mammals, most cell types have primary cilia, protruding structures involved in sensing mechanical and chemical signals from the extracellular environment that act as major communication hubs for signaling controlling cell differentiation and polarity.

Cited by 153 publications

References 40 publications

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

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Nedd9 restrains renal cystogenesis in Pkd1 ^−/− mice

Nedd9 restrains renal cystogenesis in Pkd1 ^−/− mice