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Melania Ester Mercado-Pimentel, Craig Miller, Daniela N Rolph, Edrick F Villalobos, Allison M Dunn, Prithvi M Mohan, Suzu Igarashi, Xiangdang Liu, Macken Yrun-Duffy, Neal K Patel, Cecilia M Read, Ross H Francis, Adelina Isabella Lane, Swaroop Murugesh, Abraham Jacob
HYPOTHESIS: p21-activated kinase (PAK) regulates signaling pathways that promote cell survival and proliferation; therefore, pharmacological inhibition of PAK will induce cell death in vestibular schwannomas (VS) and meningiomas. BACKGROUND: All VS and many meningiomas result from loss of the neurofibromatosis type 2 (NF2) gene product merlin, with ensuing PAK hyperactivation and increased cell proliferation/survival. METHODS: The novel small molecule PAK inhibitors PI-8 and PI-15-tested in schwannoma and meningioma cells-perturb molecular signaling and induce cell death...
October 12, 2016: Otology & Neurotology
Katie N Myers, Giancarlo Barone, Anil Ganesh, Christopher J Staples, Anna E Howard, Ryan D Beveridge, Sarah Maslen, J Mark Skehel, Spencer J Collis
It was recently discovered that vertebrate genomes contain multiple endogenised nucleotide sequences derived from the non-retroviral RNA bornavirus. Strikingly, some of these elements have been evolutionary maintained as open reading frames in host genomes for over 40 million years, suggesting that some endogenised bornavirus-derived elements (EBL) might encode functional proteins. EBLN1 is one such element established through endogenisation of the bornavirus N gene (BDV N). Here, we functionally characterise human EBLN1 as a novel regulator of genome stability...
October 14, 2016: Scientific Reports
Toshifumi Fukuda, Shun Nagashima, Takaya Abe, Hiroshi Kiyonari, Ryoko Inatome, Shigeru Yanagi
The DISC1-interacting protein CAMDI has been suggested to promote radial migration through centrosome regulation. However, its physiological relevance is unclear. Here, we report the generation and characterization of CAMDI-deficient mice. CAMDI-deficient mice exhibit delayed radial migration with aberrant neural circuit formation and psychiatric behaviors including hyperactivity, repetitive behavior, and social abnormality typically observed in autism spectrum disorder patients. Analyses of direct targets of CAMDI identify HDAC6 whose α-tubulin deacetylase activity is inhibited by CAMDI at the centrosome...
October 13, 2016: EMBO Reports
Shuai Hou, Na Li, Qian Zhang, Hui Li, Xinyue Wei, Tian Hao, Yue Li, Sikandar Azam, Caigang Liu, Wei Cheng, Bilian Jin, Quentin Liu, Man Li, Haixin Lei
Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is a multi-functional protein that plays critical role in processes including transcription, transcription-coupled DNA repair, pre-mRNA splicing, homologous recombination and mRNA export. Microarray analysis on gene expression in XAB2 knockdown cells reveals that many genes with significant change in expression function in mitotic cell cycle regulation. Fluorescence-activated cell scanner analysis confirmed XAB2 depletion led to cell arrest in G2/M phase, mostly at prophase or prometaphase...
October 13, 2016: Cell Death & Disease
Yoo Hong Min, Wootae Kim, Ja-Eun Kim
Mitotic progression is crucial for the maintenance of chromosomal stability. A proper progression is ensured by the activities of multiple kinases. One of these enzymes, the serine/threonine kinase Aurora A, is required for proper mitosis through the regulation of centrosome and spindle assembly. In this study, we functionally characterized a newly developed Aurora kinase A inhibitor, TC-A2317. In human lung cancer cells, TC-A2317 slowed proliferation by causing aberrant formation of centrosome and microtubule spindles and prolonging the duration of mitosis...
October 4, 2016: Oncotarget
Vincent Portegijs, Lars-Eric Fielmich, Matilde Galli, Ruben Schmidt, Javier Muñoz, Tim van Mourik, Anna Akhmanova, Albert J R Heck, Mike Boxem, Sander van den Heuvel
During cell division, the mitotic spindle segregates replicated chromosomes to opposite poles of the cell, while the position of the spindle determines the plane of cleavage. Spindle positioning and chromosome segregation depend on pulling forces on microtubules extending from the centrosomes to the cell cortex. Critical in pulling force generation is the cortical anchoring of cytoplasmic dynein by a conserved ternary complex of Gα, GPR-1/2, and LIN-5 proteins in C. elegans (Gα-LGN-NuMA in mammals). Previously, we showed that the polarity kinase PKC-3 phosphorylates LIN-5 to control spindle positioning in early C...
October 2016: PLoS Genetics
Yijun Zhang, Youguang Luo, Rui Lyu, Jie Chen, Ruming Liu, Dengwen Li, Min Liu, Jun Zhou
Cell migration, a complex process critical for tumor progression and metastasis, requires a dynamic crosstalk between microtubules (MTs) and focal adhesions (FAs). However, the molecular mechanisms underlying this event remain elusive. Herein we identify the proto-oncogenic protein Src as an important player in the regulation of the MT-FA crosstalk. Src interacts with and phosphorylates end-binding protein 1 (EB1), a member of MT plus end-tracking proteins (+TIPs), both in cells and in vitro. Systematic mutagenesis reveals that tyrosine-247 (Y247) is the primary residue of EB1 phosphorylated by Src...
2016: Theranostics
Delia Ricolo, Myrto Deligiannaki, Jordi Casanova, Sofia J Araújo
Centrosome amplification is a hallmark of cancer, although we are still far from understanding how this process affects tumorigenesis [1, 2]. Besides the contribution of supernumerary centrosomes to mitotic defects, their biological effects in the post-mitotic cell are not well known. Here, we exploit the effects of centrosome amplification in post-mitotic cells during single-cell branching. We show that Drosophila tracheal cells with extra centrosomes branch more than wild-type cells. We found that mutations in Rca1 and CycA affect subcellular branching, causing tracheal tip cells to form more than one subcellular lumen...
September 17, 2016: Current Biology: CB
E Bustos-Morán, N Blas-Rus, N B Martín-Cófreces, F Sánchez-Madrid
The immune synapse (IS) is a specialized structure established between different immune cells that fulfills several functions, including a role as a communication bridge. This intimate contact between a T cell and an antigen-presenting cell promotes the proliferation and differentiation of lymphocytes involved in the contact. T-cell activation requires the specific triggering of the T-cell receptor (TCR), which promotes the activation of different signaling pathways inducing the polarization of the T cell. During this process, different adhesion and signaling receptors reorganize at specialized membrane domains, concomitantly to the polarization of the tubulin and actin cytoskeletons, forming stable polarization platforms...
2016: International Review of Cell and Molecular Biology
Michael D Stubenvoll, Jeffrey C Medley, Miranda Irwin, Mi Hye Song
Centrosomes are critical sites for orchestrating microtubule dynamics, and exhibit dynamic changes in size during the cell cycle. As cells progress to mitosis, centrosomes recruit more microtubules (MT) to form mitotic bipolar spindles that ensure proper chromosome segregation. We report a new role for ATX-2, a C. elegans ortholog of Human Ataxin-2, in regulating centrosome size and MT dynamics. ATX-2, an RNA-binding protein, forms a complex with SZY-20 in an RNA-independent fashion. Depleting ATX-2 results in embryonic lethality and cytokinesis failure, and restores centrosome duplication to zyg-1 mutants...
September 2016: PLoS Genetics
I A Olovnikov, V V Morgunova, A A Mironova, M Y Kordyukova, E I Radion, O M Olenkina, N V Akulenko, A I Kalmykova
The telomere is a nucleoprotein complex at the ends of linear chromosomes that protects them from fusion and degradation. The telomere consists of telomeric DNA, a protective protein complex and telomeric RNA. Biogenesis of telomeric transcripts in development is still far from being understood. Drosophila telomeres are elongated by a transposition of specialized telomeric retrotransposons that encode proteins. Using transgenic constructs encoding tagged telomeric protein, we found that transcripts of Drosophila telomeric element HeT-A bind Gag-HeT-A protein encoded by these transcripts...
September 2016: Biochemistry. Biokhimii︠a︡
Jinhua Zhou, Albandri Alfraidi, Shu Zhang, Janice Santiago-O'Farrill, Venkata Yerramreddy, Abdulkhaliq Alsaadid, Ahmed Ashour Ahmed, Hailing Yang, Jinsong Liu, Weiqun Mao, Hiroshi Takemori, Yan Wang, Hariprasad Vankayalapati, Zhen Lu, Robert C Bast
PURPOSE: SIK2 is a centrosome kinase required for mitotic spindle formation and a potential target for ovarian cancer therapy. Here we examine the effects of a novel small molecule SIK2 inhibitor, ARN-3236, on sensitivity to paclitaxel in ovarian cancer. EXPERIMENTAL DESIGN: SIK2 expression was determined in ovarian cancer tissue samples and cell lines. ARN-3236 was tested for its efficiency to inhibit growth and enhance paclitaxel sensitivity in cultures and xenografts of ovarian cancer cell lines...
September 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jingchao Wu, Cecilia de Heus, Qingyang Liu, Benjamin P Bouchet, Ivar Noordstra, Kai Jiang, Shasha Hua, Maud Martin, Chao Yang, Ilya Grigoriev, Eugene A Katrukha, A F Maarten Altelaar, Casper C Hoogenraad, Robert Z Qi, Judith Klumperman, Anna Akhmanova
The Golgi apparatus controls the formation of non-centrosomal microtubule arrays important for Golgi organization, polarized transport, cell motility, and cell differentiation. Here, we show that CAMSAP2 stabilizes and attaches microtubule minus ends to the Golgi through a complex of AKAP450 and myomegalin. CLASPs stabilize CAMSAP2-decorated microtubules but are not required for their Golgi tethering. AKAP450 is also essential for Golgi microtubule nucleation, and myomegalin and CDK5RAP2 but not CAMSAP2 contribute to this function...
October 10, 2016: Developmental Cell
Antonella Sferra, Gilbert Baillat, Teresa Rizza, Sabina Barresi, Elisabetta Flex, Giorgio Tasca, Adele D'Amico, Emanuele Bellacchio, Andrea Ciolfi, Viviana Caputo, Serena Cecchetti, Annalaura Torella, Ginevra Zanni, Daria Diodato, Emanuela Piermarini, Marcello Niceta, Antonietta Coppola, Enrico Tedeschi, Diego Martinelli, Carlo Dionisi-Vici, Vincenzo Nigro, Bruno Dallapiccola, Claudia Compagnucci, Marco Tartaglia, Georg Haase, Enrico Bertini
Tubulinopathies constitute a family of neurodevelopmental/neurodegenerative disorders caused by mutations in several genes encoding tubulin isoforms. Loss-of-function mutations in TBCE, encoding one of the five tubulin-specific chaperones involved in tubulin folding and polymerization, cause two rare neurodevelopmental syndromes, hypoparathyroidism-retardation-dysmorphism and Kenny-Caffey syndrome. Although a missense mutation in Tbce has been associated with progressive distal motor neuronopathy in the pmn/pmn mice, no similar degenerative phenotype has been recognized in humans...
October 6, 2016: American Journal of Human Genetics
Ariana D Sanchez, Jessica L Feldman
The process of cellular differentiation requires the distinct spatial organization of the microtubule cytoskeleton, the arrangement of which is specific to cell type. Microtubule patterning does not occur randomly, but is imparted by distinct subcellular sites called microtubule-organizing centers (MTOCs). Since the discovery of MTOCs fifty years ago, their study has largely focused on the centrosome. All animal cells use centrosomes as MTOCs during mitosis. However in many differentiated cells, MTOC function is reassigned to non-centrosomal sites to generate non-radial microtubule organization better suited for new cell functions, such as mechanical support or intracellular transport...
September 22, 2016: Current Opinion in Cell Biology
Lan B Hoang-Minh, Loic P Deleyrolle, Nariaki S Nakamura, Alexander K Parker, Regina T Martuscello, Brent A Reynolds, Matthew R Sarkisian
A better understanding of the molecules implicated in the growth and survival of glioblastoma (GBM) cells and their response to temozolomide (TMZ), the standard-of-care chemotherapeutic agent, is necessary for the development of new therapies that would improve the outcome of current GBM treatments. In this study, we characterize the role of pericentriolar material 1 (PCM1), a component of centriolar satellites surrounding centrosomes, in GBM cell proliferation and sensitivity to genotoxic agents such as TMZ...
October 2016: Translational Oncology
Sheena Sharma, Jennifer M Kalish, Ethan M Goldberg, Francis Jeshira Reynoso, Madhura Pradhan
Background. Oral-facial-digital syndrome type 1 (OFD1) is a rare condition with X-linked dominant inheritance caused by mutations in the Cxorf5 (OFD1) gene. This gene encodes the OFD1 protein located within centrosomes and basal bodies of primary cilia. Approximately 15-50% of patients with OFD1 progress to end-stage kidney disease following development of polycystic changes within the kidneys. This condition almost always causes intrauterine lethality in males. Description of Case Diagnosis and Treatment. A Caucasian male aged 9 years and 9 months presented with increased urinary frequency, increased thirst, and decreased appetite...
2016: Case Reports in Nephrology
Makiko Tsutsumi, Setsuri Yokoi, Fuyuki Miya, Masafumi Miyata, Mitsuhiro Kato, Nobuhiko Okamoto, Tatsuhiko Tsunoda, Mami Yamasaki, Yonehiro Kanemura, Kenjiro Kosaki, Shinji Saitoh, Hiroki Kurahashi
It has been well documented that variants in genes encoding centrosomal proteins cause primary autosomal recessive microcephaly, although the association between centrosomal defects and the etiology of microcephaly syndromes is not fully understood. Polo-like kinase 4 (PLK4) is one of the centrosomal proteins required for centriole duplication. We here describe a patient with microcephaly and chorioretinopathy that harbors compound heterozygous missense variants, c.[442A>G]; [2336G>A], in the PLK4 gene...
September 21, 2016: European Journal of Human Genetics: EJHG
Anna A Ye, Julia Torabi, Thomas J Maresca
During cytokinesis, aurora B kinase (ABK) relocalizes from centromeres to the spindle midzone, where it is thought to provide a spatial cue for cytokinesis. While global ABK inhibition in Drosophila S2 cells results in macro- and multi-nucleated large cells, mislocalization of midzone ABK (mABK) by depletion of Subito (Drosophila MKLP2) does not cause notable cytokinesis defects. Subito depletion was, therefore, used to investigate the contribution of other molecules and redundant pathways to cytokinesis in the absence of mABK...
August 2016: Biological Bulletin
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