scholarly journals Trichoplein and Aurora A block aberrant primary cilia assembly in proliferating cells

2012 ◽  
Vol 197 (3) ◽  
pp. 391-405 ◽  
Author(s):  
Akihito Inoko ◽  
Makoto Matsuyama ◽  
Hidemasa Goto ◽  
Yuki Ohmuro-Matsuyama ◽  
Yuko Hayashi ◽  
...  
Keyword(s):  
Primary Cilia ◽  
G1 Arrest ◽  
Aurora A ◽  
Proliferating Cells ◽  
Quiescent Cells ◽  
Cilia Formation ◽  
Mother And Daughter ◽  
Exogenous Expression ◽  
Sensory Functions

The primary cilium is an antenna-like organelle that modulates differentiation, sensory functions, and signal transduction. After cilia are disassembled at the G0/G1 transition, formation of cilia is strictly inhibited in proliferating cells. However, the mechanisms of this inhibition are unknown. In this paper, we show that trichoplein disappeared from the basal body in quiescent cells, whereas it localized to mother and daughter centrioles in proliferating cells. Exogenous expression of trichoplein inhibited primary cilia assembly in serum-starved cells, whereas ribonucleic acid interference–mediated depletion induced primary cilia assembly upon cultivation with serum. Trichoplein controlled Aurora A (AurA) activation at the centrioles predominantly in G1 phase. In vitro analyses confirmed that trichoplein bound and activated AurA directly. Using trichoplein mutants, we demonstrate that the suppression of primary cilia assembly by trichoplein required its ability not only to localize to centrioles but also to bind and activate AurA. Trichoplein or AurA knockdown also induced G0/G1 arrest, but this phenotype was reversed when cilia formation was prevented by simultaneous knockdown of IFT-20. These data suggest that the trichoplein–AurA pathway is required for G1 progression through a key role in the continuous suppression of primary cilia assembly.

scholarly journals Ndel1 suppresses ciliogenesis in proliferating cells by regulating the trichoplein–Aurora A pathway

2016 ◽  
Vol 212 (4) ◽  
pp. 409-423 ◽  
Author(s):  
Hironori Inaba ◽  
Hidemasa Goto ◽  
Kousuke Kasahara ◽  
Kanako Kumamoto ◽  
Shigenobu Yonemura ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Serum Starvation ◽  
Aurora A ◽  
Proliferating Cells ◽  
Quiescent Cells ◽  
Cell Cycle Reentry ◽  
Upstream Regulator ◽  
Cilia Formation ◽  
Mother Centriole ◽  
Component Protein

Primary cilia protrude from the surface of quiescent cells and disassemble at cell cycle reentry. We previously showed that ciliary reassembly is suppressed by trichoplein-mediated Aurora A activation pathway in growing cells. Here, we report that Ndel1, a well-known modulator of dynein activity, localizes at the subdistal appendage of the mother centriole, which nucleates a primary cilium. In the presence of serum, Ndel1 depletion reduces trichoplein at the mother centriole and induces unscheduled primary cilia formation, which is reverted by forced trichoplein expression or coknockdown of KCTD17 (an E3 ligase component protein for trichoplein). Serum starvation induced transient Ndel1 degradation, subsequent to the disappearance of trichoplein at the mother centriole. Forced expression of Ndel1 suppressed trichoplein degradation and axonemal microtubule extension during ciliogenesis, similar to trichoplein induction or KCTD17 knockdown. Most importantly, the proportion of ciliated and quiescent cells was increased in the kidney tubular epithelia of newborn Ndel1-hypomorphic mice. Thus, Ndel1 acts as a novel upstream regulator of the trichoplein–Aurora A pathway to inhibit primary cilia assembly.

scholarly journals KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Petra Pejskova ◽  
Madeline Louise Reilly ◽  
Lucia Bino ◽  
Ondrej Bernatik ◽  
Linda Dolanska ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Cell Cycle Progression ◽  
Primary Cilia ◽  
Aurora A ◽  
Pathway Activation ◽  
Cilia Formation ◽  
Tightly Coupled ◽  
Hh Signaling

Primary cilia play critical roles in development and disease. Their assembly and disassembly are tightly coupled to cell cycle progression. Here, we present data identifying KIF14 as a regulator of cilia formation and Hedgehog (HH) signaling. We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. We identify deregulated Aurora A activity as a mechanism contributing to the primary cilium and BB formation defects seen after KIF14 depletion. In addition, we show that primary cilia in KIF14-depleted cells are defective in response to HH pathway activation, independently of the effects of Aurora A. In sum, our data point to KIF14 as a critical node connecting cell cycle machinery, effective ciliogenesis, and HH signaling.

scholarly journals Prdx1 Promotes the Loss of Primary Cilia in Esophageal Squamous Cell Carcinoma

2019 ◽  
Author(s):  
Fanghua Gong ◽  
Qiongzhen Chen ◽  
Jinmeng Li ◽  
Xiaoning Yang ◽  
Junfeng Ma ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Tumor Formation ◽  
Aurora A ◽  
Cilia Formation ◽  
Signaling Axis

Abstract Background: Loss of primary cilia is frequently observed in tumor cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction, the inability to exit the cell cycle, and promotion of tumor cell invasion. Primary cilia loss also occurs in esophageal squamous cell carcinoma (ESCC) cells, but the molecular mechanisms that explain how ESCC cells lose primary cilia remain poorly understood. Methods: Inhibiting the expression of Prdx1 in the ESCC cells to detect the up-regulated genes related to cilium regeneration and down-regulated genes related to cilium disassembly by Gene chip. And, mice and cell experiments were carried to confirm the role of the HEF1-Aurora A-HDAC6 signaling axis in ESCC. Results: In this study, we found that silencing Peroxiredoxin 1 (Prdx1) restores primary cilia formation, and over-expressing Prdx1 induces primary cilia loss in ESCC cells. We also showed that the expression of Prdx1 regulates the action of the HEF1-Aurora A-HDAC6 signaling axis to promote the disassembly of primary cilia, and suppression of Prdx1 results in decreased tumor formation and tumor mass volume in vivo. Conclusions: These results suggest that Prdx1 is a novel regulator of primary cilia formation in ESCC cells.

scholarly journals Trichoplein keeps primary cilia silent

2012 ◽  
Vol 197 (3) ◽  
pp. 341-341 ◽  
Author(s):  
Ben Short
Keyword(s):  
Primary Cilia ◽  
Aurora A ◽  
Proliferating Cells

Study identifies a centriolar protein that activates Aurora A to suppress ciliogenesis in proliferating cells.

scholarly journals Aurora A and AKT Kinase Signaling Associated with Primary Cilia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3602
Author(s):  
Yuhei Nishimura ◽  
Daishi Yamakawa ◽  
Takashi Shiromizu ◽  
Masaki Inagaki
Keyword(s):  
Primary Cilia ◽  
Tissue Type ◽  
Aurora A ◽  
Kinase Signaling ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
Cell Tissue ◽  
Selective Targeting ◽  
Cilia Formation ◽  
And Function

Dysregulation of kinase signaling is associated with various pathological conditions, including cancer, inflammation, and autoimmunity; consequently, the kinases involved have become major therapeutic targets. While kinase signaling pathways play crucial roles in multiple cellular processes, the precise manner in which their dysregulation contributes to disease is dependent on the context; for example, the cell/tissue type or subcellular localization of the kinase or substrate. Thus, context-selective targeting of dysregulated kinases may serve to increase the therapeutic specificity while reducing off-target adverse effects. Primary cilia are antenna-like structures that extend from the plasma membrane and function by detecting extracellular cues and transducing signals into the cell. Cilia formation and signaling are dynamically regulated through context-dependent mechanisms; as such, dysregulation of primary cilia contributes to disease in a variety of ways. Here, we review the involvement of primary cilia-associated signaling through aurora A and AKT kinases with respect to cancer, obesity, and other ciliopathies.

Effectiveness of Transcriptional CDK Inhibitors in Targeting Non-Proliferating CD34+CD38- AML Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3482-3482
Author(s):  
Monica Pallis ◽  
Francis Burrows ◽  
Abigail Whittall ◽  
Claire Seedhouse ◽  
Nicholas Boddy ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Rna Polymerase Ii ◽  
Rna Synthesis ◽  
Cdk Inhibitors ◽  
Proliferating Cells ◽  
Median Percentage ◽  
Homogeneous Population ◽  
Quiescent Cells ◽  
Species Production

Abstract Abstract 3482 Quiescent cells conserve energy and are characterised by low RNA synthesis. In contrast, cancer cells are thought to be addicted to high RNA synthesis, particularly synthesis of survival molecules. We hypothesised that quiescent cancer cells, already low in RNA, would be sensitive to apoptosis induced by transcriptional cyclin-dependent kinase (CDK) inhibitors that further deplete RNA. We cultured the CD34+CD38- KG1a cell line continuously in the presence of an mTOR inhibitor, which maintained excellent viability and enriched the cells for quiescent stem cell features including low RNA content, low metabolism, low reactive oxygen species production and decreased size. Sensitivity to mitochondrial pore transition was similar in proliferating and quiescence-enriched cells, indicating that the basal mitochondrial apoptotic machinery is neither impaired nor improved. We treated quiescence-enriched cells for 48 hours with the nucleoside analogues ara-C, 5-azacytidine and clofarabine, the topoisomerase targeting agents daunorubicin, etoposide and irinotecan and three multikinase inhibitors with activity against transcriptional CDKs - flavopiridol, roscovotine and TG02. All of the agents used showed increased kill in the unmanipulated compared to the quiescence-enriched cells, emphasising the chemoresistant nature of quiescent cells. To put a value on the difficulty of eradicating the leukamic clone, we used the parameter 2 X IC50 (which theoretically would kill 100% cells in a totally homogeneous population). In quiescence-enriched cells, the percentage of cells killed at 2 X IC50 was roscovotine - 80%, TG02 – 72%, flavopiridol - 62%, 5-azacydidine - 61%, daunorubicin, clofarabine and irinotecan - 60%, etoposide - 58%, and for araC no IC50 for quiescence-enriched cells was reached at 20 times the IC50 of proliferating cells. The data show conclusively that, in this model, transcriptional CDK inhibitors outperformed the agents conventionally used in AML chemotherapy. We also showed that transcriptional CDK inhibitors induced serine 2 dephosphorylation of RNA polymerase II in equal measure in proliferating and quiescence- enriched cells. We have already shown that TGO2 targets primary CD34+CD38- cells in vitro (ASH 2010, abstract 1823). Here we also show that in four primary AML samples sensitive to roscovotine in vitro, the median percentage kill is greater in the CD34+CD38- subset, (which consists largely of quiescent cells and tends to contain the leukaemic stem cells,) than in the bulk cells (40.5% versus 19.5% kill at 2 micromolar roscovotine). We suggest that transcriptional CDK inhibitors may be a useful class of agent for targetting the occult quiescent CD34+CD38- cells thought to contribute to relapse in AML. Disclosures: Burrows: Tragara Pharmaceuticals: Employment.

scholarly journals Enhanced Serine Palmitoyltransferase Expression in Proliferating Fibroblasts, Transformed Cell Lines, and Human Tumors

2003 ◽  
Vol 51 (6) ◽  
pp. 715-726 ◽  
Author(s):  
Jill M. Carton ◽  
David J. Uhlinger ◽  
Ameesha D. Batheja ◽  
Claudia Derian ◽  
George Ho ◽  
...  
Keyword(s):  
Wound Repair ◽  
Cell Activity ◽  
Serine Palmitoyltransferase ◽  
Proliferating Cells ◽  
Stromal Fibroblasts ◽  
Quiescent Cells ◽  
Cell Metastasis ◽  
Vitro Model ◽  
Transformed Cell Lines

Metastatic processes, including cell invasion, extracellular matrix degradation, and tissue remodeling, require cellular reorganization and proliferation. The cell signaling molecules required and the proteins involved in cell restructuring have not been completely elucidated. We have been studying the role of sphingolipids in normal cell activity and in several pathophysiological states. In this study we used immunohistochemistry to observe the presence of the two known subunits of serine palmitoyltransferase (SPT) in proliferating cells, in an in vitro model of wound repair, and in human malignant tissue. We report increased expression of the two subunits, SPT1 and SPT2, in the proliferating cells in these models. We also demonstrate a change in subcellular localization of the SPT subunits from predominantly cytosolic in quiescent cells to nuclear in proliferating cells. In addition, we observed SPT1 and SPT2 immunoreactivity in reactive stromal fibroblasts surrounding the carcinoma cells of some of the tumors. This enhanced SPT expression was absent in the stromal fibroblasts surrounding normal epithelial cells. Our results suggest a potential role for overexpression of SPT in the processes of cell metastasis.

scholarly journals CycleFlow quantifies cell-cycle heterogeneity in vivo

2020 ◽  
Author(s):  
Adrien Jolly ◽  
Ann-Kathrin Fanti ◽  
Ines Gräßer ◽  
Nils B. Becker ◽  
Thomas Höfer
Keyword(s):  
Cell Cycle ◽  
Cycle Length ◽  
Proliferating Cells ◽  
Average Cell ◽  
Quiescent Cells ◽  
A Cell ◽  
Cell Cycle Length ◽  
Combined Measurements

AbstractWhile the average cell-cycle length in a cell population can be derived from pulse-chase experiments, proliferative heterogeneity has been difficult to quantify. Here we describe CycleFlow, a broadly applicable method that applies Bayesian inference to combined measurements of EdU incorporation and DNA content. CycleFlow accurately quantifies the fraction of proliferating versus quiescent cells and the durations of cell-cycle phases of the proliferating cells in vitro and in vivo.

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