scholarly journals CEP55 promotes cilia disassembly through stabilizing Aurora A kinase

2021 ◽  
Vol 220 (2) ◽  
Author(s):  
Yu-Cheng Zhang ◽  
Yun-Feng Bai ◽  
Jin-Feng Yuan ◽  
Xiao-Lin Shen ◽  
Yu-Ling Xu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Primary Cilia ◽  
Perinatal Death ◽  
Clinical Manifestations ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Mammalian Development ◽  
Polycystic Kidneys ◽  
And Control

Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55−/− mice display clinical manifestations of Meckel–Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55−/− mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel–Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.

scholarly journals MLN8054, an Inhibitor of Aurora A Kinase, Induces Senescence in Human Tumor Cells Both In vitro and In vivo

2010 ◽  
Vol 8 (3) ◽  
pp. 373-384 ◽  
Author(s):  
Jessica J. Huck ◽  
Mengkun Zhang ◽  
Alice McDonald ◽  
Doug Bowman ◽  
Kara M. Hoar ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Human Tumor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Human Tumor Cells

A Novel Small Molecule Inhibitor for Aurora-A Kinase Inhibits the Growth of Cervical Cancer In Vitro and In Vivo.

2010 ◽  
Vol 83 (Suppl_1) ◽  
pp. 344-344
Author(s):  
Patricia Y. Akinfenwa ◽  
Nonna V. Kolomeyevskaya ◽  
Claire M. Mach ◽  
Zhen Li ◽  
Matthew L. Anderson
Keyword(s):  
Cervical Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Molecule Inhibitor

scholarly journals Interaction of Aurora-A and centrosomin at the microtubule-nucleating site in Drosophila and mammalian cells

2003 ◽  
Vol 162 (5) ◽  
pp. 757-764 ◽  
Author(s):  
Yasuhiko Terada ◽  
Yumi Uetake ◽  
Ryoko Kuriyama
Keyword(s):  
Mammalian Cells ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Mitotic Spindles ◽  
Microtubule Nucleation ◽  
Microtubule Organization ◽  
Centrosomal Protein ◽  
Spindle Poles

A mitosis-specific Aurora-A kinase has been implicated in microtubule organization and spindle assembly in diverse organisms. However, exactly how Aurora-A controls the microtubule nucleation onto centrosomes is unknown. Here, we show that Aurora-A specifically binds to the COOH-terminal domain of a Drosophila centrosomal protein, centrosomin (CNN), which has been shown to be important for assembly of mitotic spindles and spindle poles. Aurora-A and CNN are mutually dependent for localization at spindle poles, which is required for proper targeting of γ-tubulin and other centrosomal components to the centrosome. The NH2-terminal half of CNN interacts with γ-tubulin, and induces cytoplasmic foci that can initiate microtubule nucleation in vivo and in vitro in both Drosophila and mammalian cells. These results suggest that Aurora-A regulates centrosome assembly by controlling the CNN's ability to targeting and/or anchoring γ-tubulin to the centrosome and organizing microtubule-nucleating sites via its interaction with the COOH-terminal sequence of CNN.

scholarly journals Human TPX2 is required for targeting Aurora-A kinase to the spindle

2002 ◽  
Vol 158 (4) ◽  
pp. 617-623 ◽  
Author(s):  
Thomas A. Kufer ◽  
Herman H.W. Silljé ◽  
Roman Körner ◽  
Oliver J. Gruss ◽  
Patrick Meraldi ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Major Protein ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Binding Studies ◽  
Serine Threonine Kinase ◽  
Cell Extracts ◽  
Prominent Component ◽  
Spindle Apparatus

Aurora-A is a serine-threonine kinase implicated in the assembly and maintenance of the mitotic spindle. Here we show that human Aurora-A binds to TPX2, a prominent component of the spindle apparatus. TPX2 was identified by mass spectrometry as a major protein coimmunoprecipitating specifically with Aurora-A from mitotic HeLa cell extracts. Conversely, Aurora-A could be detected in TPX2 immunoprecipitates. This indicates that subpopulations of these two proteins undergo complex formation in vivo. Binding studies demonstrated that the NH2 terminus of TPX2 can directly interact with the COOH-terminal catalytic domain of Aurora-A. Although kinase activity was not required for this interaction, TPX2 was readily phosphorylated by Aurora-A. Upon siRNA-mediated elimination of TPX2 from cells, the association of Aurora-A with the spindle microtubules was abolished, although its association with spindle poles was unaffected. Conversely, depletion of Aurora-A by siRNA had no detectable influence on the localization of TPX2. We propose that human TPX2 is required for targeting Aurora-A kinase to the spindle apparatus. In turn, Aurora-A might regulate the function of TPX2 during spindle assembly.

scholarly journals The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Saishu Yoshida ◽  
Katsuhiko Aoki ◽  
Ken Fujiwara ◽  
Takashi Nakakura ◽  
Akira Kawamura ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
The Novel ◽  
Mammalian Development ◽  
Hh Signaling ◽  
Functional Analyses ◽  
First Time ◽  
Insight Into

Mammalian Hedgehog (Hh) signaling plays key roles in embryogenesis and uniquely requires primary cilia. Functional analyses of several ciliogenesis-related genes led to the discovery of the developmental diseases known as ciliopathies. Hence, identification of mammalian factors that regulate ciliogenesis can provide insight into the molecular mechanisms of embryogenesis and ciliopathy. Here, we demonstrate that DYRK2 acts as a novel mammalian ciliogenesis-related protein kinase. Loss of Dyrk2 in mice causes suppression of Hh signaling and results in skeletal abnormalities during in vivo embryogenesis. Deletion of Dyrk2 induces abnormal ciliary morphology and trafficking of Hh pathway components. Mechanistically, transcriptome analyses demonstrate down-regulation of Aurka and other disassembly genes following Dyrk2 deletion. Taken together, the present study demonstrates for the first time that DYRK2 controls ciliogenesis and is necessary for Hh signaling during mammalian development.

Sex-dependent Effects of Nephron Ift88 Disruption on Blood Pressure, Renal Function and Cystogenesis

2021 ◽  
pp. ASN.2020111571
Author(s):  
Chunyan Hu ◽  
Jayalakshmi Lakshmipathi ◽  
Elizabeth Binning ◽  
Kelly Hyndman ◽  
Deborah Stuart ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Primary Cilia ◽  
Plasma Renin ◽  
Cyst Formation ◽  
Renal Physiology ◽  
No Production ◽  
Polycystic Kidneys ◽  
Nitrite Nitrate ◽  
And Control

Background: Primary cilia regulation of renal function and blood pressure (BP) in health and disease is incompletely understood. The current study investigated the effect of nephron ciliary loss on renal physiology, blood pressure and ensuing cystogenesis. Methods: Mice underwent doxycycline (DOX)-inducible nephron-specific knockout (KO) of the Ift88 gene at 2 months of age using a Cre-LoxP strategy. Blood pressure, kidney function, and renal pathology were studied 2 and 9 months after DOX (Ift88 KO) or vehicle (control). Results: At 2 months post DOX, male, but not female, Ift88 KO, compared to sex-matched control, mice had reduced BP, enhanced salt-induced natriuresis, increased urinary nitrite/nitrate (NOx) excretion, and increased kidney NOS3 levels which localized to the outer medulla; the reductions in BP in male mice were prevented by L-NAME. At 9 months post DOX, male, but not female, Ift88 KO mice had polycystic kidneys, elevated BP and reduced urinary NOx excretion. No differences were observed in plasma renin concentration, plasma aldosterone, urine vasopressin or urine PGE2 between Ift88 KO and control mice at 2 or 9 months post DOX. Conclusions: Nephron cilia disruption in male, but not female, mice: 1) reduces BP prior to cyst formation; 2) increases NOx production that may account for the lower BP prior to cyst formation; and 3) induces polycystic kidneys that are associated with hypertension and reduced renal NO production.

scholarly journals Extracellular distribution of diffusible growth factors controlled by heparan sulfate proteoglycans during mammalian embryogenesis

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130545 ◽  
Author(s):  
Isao Matsuo ◽  
Chiharu Kimura-Yoshida
Keyword(s):  
Growth Factors ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Cell Fate ◽  
Heparan Sulfate Proteoglycans ◽  
Target Cells ◽  
Dependent Manner ◽  
Mammalian Development ◽  
Morphogenetic Protein ◽  
And Control

During mouse embryogenesis, diffusible growth factors, i.e. fibroblast growth factors, Wnt, bone morphogenetic protein and Hedgehog family members, emanating from localized areas can travel through the extracellular space and reach their target cells to specify the cell fate and form tissue architectures in coordination. However, the mechanisms by which these growth factors travel great distances to their target cells and control the signalling activity as morphogens remain an enigma. Recent studies in mice and other model animals have revealed that heparan sulfate proteoglycans (HSPGs) located on the cell surface (e.g. syndecans and glypicans) and in the extracellular matrix (ECM; e.g. perlecan and agrin) play crucial roles in the extracellular distribution of growth factors. Principally, the function of HSPGs depends primarily on the fine features and localization of their heparan sulfate glycosaminoglycan chains. Cell-surface-tethered HSPGs retain growth factors as co-receptors and/or endocytosis mediators, and enzymatic release of HSPGs from the cell membrane allows HSPGs to transport or move multiple growth factors. By contrast, ECM-associated HSPGs function as a reservoir or barrier in a context-dependent manner. This review is focused on our current understanding of the extracellular distribution of multiple growth factors controlled by HSPGs in mammalian development.

scholarly journals Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues

2007 ◽  
Vol 14 (3) ◽  
pp. 827-837 ◽  
Author(s):  
Salvatore Ulisse ◽  
Enke Baldini ◽  
Matteo Toller ◽  
Jean-Guy Delcros ◽  
Aurélie Guého ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Cancer ◽  
Coiled Coil ◽  
Human Thyroid ◽  
Mrna Levels ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Thyroid Cells ◽  
Cancer Tissues

Aurora-A kinase has recently been shown to be deregulated in thyroid cancer cells and tissues. Among the Aurora-A substrates identified, transforming acidic coiled-coil (TACC3), a member of the TACC family, plays an important role in cell cycle progression and alterations of its expression occur in different cancer tissues. In this study, we demonstrated the expression of the TACC3 gene in normal human thyroid cells (HTU5), and its modulation at both mRNA and protein levels during cell cycle. Its expression was found, with respect to HTU5 cells, unchanged in cells derived from a benign thyroid follicular tumor (HTU42), and significantly reduced in cell lines derived from follicular (FTC-133), papillary (B-CPAP), and anaplastic thyroid carcinomas (CAL-62 and 8305C). Moreover, in 16 differentiated thyroid cancer tissues, TACC3 mRNA levels were found, with respect to normal matched tissues, reduced by twofold in 56% of cases and increased by twofold in 44% of cases. In the same tissues, a correlation between the expression of the TACC3 and Aurora-A mRNAs was observed. TACC3 and Aurora-A interact in vivo in thyroid cells and both proteins localized onto the mitotic structure of thyroid cells. Finally, TACC3 localization on spindle microtubule was no more observed following the inhibition of Aurora kinase activity by VX-680. We propose that Aurora-A and TACC3 interaction is important to control the mitotic spindle organization required for proper chromosome segregation.

scholarly journals Identification of Cilia in Different Mouse Tissues

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1623
Author(s):  
Xinhua Li ◽  
Shuting Yang ◽  
Vishwa Deepk ◽  
Zahra Chinipardaz ◽  
Shuying Yang
Keyword(s):  
Cell Surface ◽  
Primary Cilia ◽  
Apical Cell ◽  
Extracellular Fluid ◽  
Mouse Tissues ◽  
Dual Reporter ◽  
The Brain ◽  
Postnatal Stage ◽  
Comprehensive Study

Cilia are microtubule-based hair-like organelles that extend from the cell surface. However, the existence and distribution of cilia in each organ and tissue at the postnatal stage in vivo remain largely unknown. In this study, we defined cilia distribution and arrangement and measured the ciliary lengths and the percentage of ciliated cells in different organs and tissues in vivo by using cilium dual reporter-expressing transgenic mice. Cilia were identified by the presence of ARL13B with an mCherry+ signal, and the cilium basal body was identified by the presence of Centrin2 with a GFP+ signal. Here, we provide in vivo evidence that chondrocytes and cells throughout bones have cilia. Most importantly, we reveal that: 1. primary cilia are present in hepatocytes; 2. no cilia but many centrioles are distributed on the apical cell surface in the gallbladder, intestine, and thyroid epithelia; 3. cilia on the cerebral cortex are well oriented, pointing to the center of the brain; 4. ARL13B+ inclusion is evident in the thyroid and islets of Langerhans; and 5. approximately 2% of cilia show irregular movement in nucleus pulposus extracellular fluid. This study reveals the existence and distribution of cilia and centrioles in different tissues and organs, and provides new insights for further comprehensive study of ciliary function in these organs and tissues.

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