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Results: 1 to 6 of 6

Publication Record


Microtubules regulate brush border formation.
Tonucci FM, Ferretti A, Almada E, Cribb P, Vena R, Hidalgo F, Favre C, Tyska MJ, Kaverina I, Larocca MC
(2018) J Cell Physiol 233: 1468-1480
MeSH Terms: Actin Cytoskeleton, Animals, Cell Polarity, Centromere, Colon, Dogs, Enterocytes, Epithelial Cells, Humans, Kidney, Madin Darby Canine Kidney Cells, Microtubule-Associated Proteins, Microtubules, Microvilli, Nocodazole, Time Factors, Tubulin Modulators
Show Abstract · Added April 10, 2018
Most epithelial cells contain apical membrane structures associated to bundles of actin filaments, which constitute the brush border. Whereas microtubule participation in the maintenance of the brush border identity has been characterized, their contribution to de novo microvilli organization remained elusive. Hereby, using a cell model of individual enterocyte polarization, we found that nocodazole induced microtubule depolymerization prevented the de novo brush border formation. Microtubule participation in brush border actin organization was confirmed in polarized kidney tubule MDCK cells. We also found that centrosome, but not Golgi derived microtubules, were essential for the initial stages of brush border development. During this process, microtubule plus ends acquired an early asymmetric orientation toward the apical membrane, which clearly differs from their predominant basal orientation in mature epithelia. In addition, overexpression of the microtubule plus ends associated protein CLIP170, which regulate actin nucleation in different cell contexts, facilitated brush border formation. In combination, the present results support the participation of centrosomal microtubule plus ends in the activation of the polarized actin organization associated to brush border formation, unveiling a novel mechanism of microtubule regulation of epithelial polarity.
© 2017 Wiley Periodicals, Inc.
0 Communities
1 Members
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MeSH Terms
Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
Lee HH, Leake BF, Teft W, Tirona RG, Kim RB, Ho RH
(2015) Mol Cancer Ther 14: 994-1003
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Antineoplastic Agents, Biological Transport, Cell Line, Tumor, Docetaxel, Humans, Liver, Liver-Specific Organic Anion Transporter 1, Male, Mice, Mice, Knockout, Organic Anion Transporters, Organic Anion Transporters, Sodium-Independent, Rats, Solute Carrier Organic Anion Transporter Family Member 1B3, Taxoids, Tubulin Modulators
Show Abstract · Added February 25, 2015
The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.
©2015 American Association for Cancer Research.
0 Communities
2 Members
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18 MeSH Terms
Microtubule segment stabilization by RASSF1A is required for proper microtubule dynamics and Golgi integrity.
Arnette C, Efimova N, Zhu X, Clark GJ, Kaverina I
(2014) Mol Biol Cell 25: 800-10
MeSH Terms: Apoptosis, Cell Division, Cell Line, Transformed, Cell Polarity, Epithelial Cells, Gene Expression, Golgi Apparatus, Humans, Microtubules, Nocodazole, RNA, Small Interfering, Retinal Pigment Epithelium, Time-Lapse Imaging, Tubulin, Tubulin Modulators, Tumor Suppressor Proteins
Show Abstract · Added March 20, 2014
The tumor suppressor and microtubule-associated protein Ras association domain family 1A (RASSF1A) has a major effect on many cellular processes, such as cell cycle progression and apoptosis. RASSF1A expression is frequently silenced in cancer and is associated with increased metastasis. Therefore we tested the hypothesis that RASSF1A regulates microtubule organization and dynamics in interphase cells, as well as its effect on Golgi integrity and cell polarity. Our results show that RASSF1A uses a unique microtubule-binding pattern to promote site-specific microtubule rescues, and loss of RASSF1A leads to decreased microtubule stability. Furthermore, RASSF1A-associated stable microtubule segments are necessary to prevent Golgi fragmentation and dispersal in cancer cells and maintain a polarized cell front. These results indicate that RASSF1A is a key regulator in the fine tuning of microtubule dynamics in interphase cells and proper Golgi organization and cell polarity.
0 Communities
1 Members
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16 MeSH Terms
Murine CENP-F regulates centrosomal microtubule nucleation and interacts with Hook2 at the centrosome.
Moynihan KL, Pooley R, Miller PM, Kaverina I, Bader DM
(2009) Mol Biol Cell 20: 4790-803
MeSH Terms: Animals, COS Cells, Cell Line, Centrosome, Cercopithecus aethiops, Chromosomal Proteins, Non-Histone, Humans, Mice, Mice, Knockout, Microfilament Proteins, Microtubule-Associated Proteins, Microtubule-Organizing Center, Microtubules, Nocodazole, Tubulin Modulators, Two-Hybrid System Techniques
Show Abstract · Added December 10, 2013
The microtubule (MT) network is essential in a broad spectrum of cellular functions. Many studies have linked CENP-F to MT-based activities as disruption of this protein leads to major changes in MT structure and function. Still, the basis of CENP-F regulation of the MT network remains elusive. Here, our studies reveal a novel and critical localization and role for CENP-F at the centrosome, the major MT organizing center (MTOC) of the cell. Using a yeast two-hybrid screen, we identify Hook2, a linker protein that is essential for regulation of the MT network at the centrosome, as a binding partner of CENP-F. With recently developed immunochemical reagents, we confirm this interaction and reveal the novel localization of CENP-F at the centrosome. Importantly, in this first report of CENP-F(-/-) cells, we demonstrate that ablation of CENP-F protein function eliminates MT repolymerization after standard nocodazole treatment. This inhibition of MT regrowth is centrosome specific because MT repolymerization is readily observed from the Golgi in CENP-F(-/-) cells. The centrosome-specific function of CENP-F in the regulation of MT growth is confirmed by expression of truncated CENP-F containing only the Hook2-binding domain. Furthermore, analysis of partially reconstituted MTOC asters in cells that escape complete repolymerization block shows that disruption of CENP-F function impacts MT nucleation and anchoring rather than promoting catastrophe. Our study reveals a major new localization and function of CENP-F at the centrosome that is likely to impact a broad array of MT-based actions in the cell.
2 Communities
2 Members
0 Resources
16 MeSH Terms
AKAP350 modulates microtubule dynamics.
Larocca MC, Jin M, Goldenring JR
(2006) Eur J Cell Biol 85: 611-9
MeSH Terms: A Kinase Anchor Proteins, Adaptor Proteins, Signal Transducing, Centrosome, Cytoskeletal Proteins, Cytoskeleton, Down-Regulation, Gene Expression, HeLa Cells, Humans, Microtubules, Nocodazole, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Tubulin Modulators, cdc42 GTP-Binding Protein
Show Abstract · Added October 7, 2013
AKAP350 is a multiply spliced type II protein kinase A-anchoring protein that localizes to the centrosomes in most cells and the Golgi apparatus in epithelial cells. Multiple studies suggest that AKAP350 is involved in microtubule nucleation at the centrosome. Our previous studies demonstrated that AKAP350 was necessary for the maintenance of Golgi apparatus integrity. These data suggested that AKAP350 might be necessary for normal cytoskeletal interactions with the Golgi. To examine the relationship of AKAP350 with the microtubule cytoskeleton, we analyzed the effect of the depletion of AKAP350 on microtubule regrowth after nocodazole treatment in HeLa cells. The decrease in AKAP350 expression with short interfering RNA induced a delay in microtubule elongation with no effect on microtubule aster formation. In contrast, overexpression of the centrosomal targeting domain of AKAP350 elicited alterations in aster formation, but did not affect microtubule elongation. RNA interference for AKAP350 also induced an increase in cdc42 activity during microtubule regrowth. Our data suggest that AKAP350 has a role in the remodeling of the microtubule cytoskeleton.
1 Communities
1 Members
0 Resources
16 MeSH Terms
Diminished taxol/GTP-stimulated tubulin polymerization in diseased region of brain from patients with late-onset or inherited Alzheimer's disease or frontotemporal dementia with parkinsonism linked to chromosome-17 but not individuals with mild cognitive impairment.
Boutté AM, Neely MD, Bird TD, Montine KS, Montine TJ
(2005) J Alzheimers Dis 8: 1-6
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Brain, Chromosomes, Human, Pair 17, Cognition Disorders, DNA Mutational Analysis, Dementia, Female, Genetic Linkage, Humans, Male, Membrane Proteins, Microtubule-Associated Proteins, Microtubules, Paclitaxel, Parkinsonian Disorders, Presenilin-2, Tubulin, Tubulin Modulators, tau Proteins
Show Abstract · Added September 13, 2014
Neuronal microtubules are morphologically abnormal in diseased regions of brain from patients with late-onset Alzheimer's disease (LOAD). Here we tested the hypothesis that tubulin derived from gray matter of patients with multiple forms of dementia was functionally impaired. Following taxol/GTP stimulation of tubulin polymerization of gray matter extracts we observed reduced capacity of tubulin to polymerize in LOAD, but not individuals with mild cognitive impairment (MCI), compared to controls. Moreover, we observed similarly reduced taxol/GTP-stimulated tubulin polymerization from gray matter obtained from patients with AD caused by PSEN2 N141I mutation or frontotemporal dementia with parkinsonism linked to chromosome-17 caused (FTDP-17) by TAU V337M or P301L mutation. Our results show that modification of tubulin function may contribute to intermediate or late stages in the pathogenesis of sporadic and inherited AD as well as FTDP-17.
0 Communities
1 Members
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21 MeSH Terms