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1
Bone, Courtney R., Erin C. Tapley, Mátyás Gorjánácz, and Daniel A. Starr. "The Caenorhabditis elegans SUN protein UNC-84 interacts with lamin to transfer forces from the cytoplasm to the nucleoskeleton during nuclear migration." Molecular Biology of the Cell 25, no. 18 (September 15, 2014): 2853–65. http://dx.doi.org/10.1091/mbc.e14-05-0971.
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Nuclear migration is a critical component of many cellular and developmental processes. The nuclear envelope forms a barrier between the cytoplasm, where mechanical forces are generated, and the nucleoskeleton. The LINC complex consists of KASH proteins in the outer nuclear membrane and SUN proteins in the inner nuclear membrane that bridge the nuclear envelope. How forces are transferred from the LINC complex to the nucleoskeleton is poorly understood. The Caenorhabditis elegans lamin, LMN-1, is required for nuclear migration and interacts with the nucleoplasmic domain of the SUN protein UNC-84. This interaction is weakened by the unc-84(P91S) missense mutation. These mutant nuclei have an intermediate nuclear migration defect—live imaging of nuclei or LMN-1::GFP shows that many nuclei migrate normally, others initiate migration before subsequently failing, and others fail to begin migration. At least one other component of the nucleoskeleton, the NET5/Samp1/Ima1 homologue SAMP-1, plays a role in nuclear migration. We propose a nut-and-bolt model to explain how forces are dissipated across the nuclear envelope during nuclear migration. In this model, SUN/KASH bridges serve as bolts through the nuclear envelope, and nucleoskeleton components LMN-1 and SAMP-1 act as both nuts and washers on the inside of the nucleus.
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Denais, C. M., R. M. Gilbert, P. Isermann, A. L. McGregor, M. te Lindert, B. Weigelin, P. M. Davidson, P. Friedl, K. Wolf, and J. Lammerding. "Nuclear envelope rupture and repair during cancer cell migration." Science 352, no. 6283 (March 24, 2016): 353–58. http://dx.doi.org/10.1126/science.aad7297.
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Fridolfsson, Heidi N., and Daniel A. Starr. "Kinesin-1 and dynein at the nuclear envelope mediate the bidirectional migrations of nuclei." Journal of Cell Biology 191, no. 1 (October 4, 2010): 115–28. http://dx.doi.org/10.1083/jcb.201004118.
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Kinesin-1 and dynein are recruited to the nuclear envelope by the Caenorhabditis elegans klarsicht/ANC-1/Syne homology (KASH) protein UNC-83 to move nuclei. The mechanisms of how these motors are coordinated to mediate nuclear migration are unknown. Time-lapse differential interference contrast and fluorescence imaging of embryonic hypodermal nuclear migration events were used to characterize the kinetics of nuclear migration and determine microtubule dynamics and polarity. Wild-type nuclei display bidirectional movements during migration and are also able to roll past cytoplasmic granules. unc-83, unc-84, and kinesin-1 mutants have severe nuclear migration defects. Without dynein, nuclear migration initiates normally but lacks bidirectional movement and shows defects in nuclear rolling, implicating dynein in resolution of cytoplasmic roadblocks. Microtubules are highly dynamic during nuclear migration. EB1::green fluorescence protein imaging demonstrates that microtubules are polarized in the direction of nuclear migration. This organization of microtubules fits with our model that kinesin-1 moves nuclei forward and dynein functions to move nuclei backward for short stretches to bypass cellular roadblocks.
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McGee, Matthew D., Regina Rillo, Amy S. Anderson, and Daniel A. Starr. "UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84." Molecular Biology of the Cell 17, no. 4 (April 2006): 1790–801. http://dx.doi.org/10.1091/mbc.e05-09-0894.
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UNC-84 is required to localize UNC-83 to the nuclear envelope where it functions during nuclear migration. A KASH domain in UNC-83 was identified. KASH domains are conserved in the nuclear envelope proteins Syne/nesprins, Klarsicht, MSP-300, and ANC-1. Caenorhabditis elegans UNC-83 was shown to localize to the outer nuclear membrane and UNC-84 to the inner nuclear membrane in transfected mammalian cells, suggesting the KASH and SUN protein targeting mechanisms are conserved. Deletion of the KASH domain of UNC-83 blocked nuclear migration and localization to the C. elegans nuclear envelope. Some point mutations in the UNC-83 KASH domain disrupted nuclear migration, even if they localized normally. At least two separable portions of the C-terminal half of UNC-84 were found to interact with the UNC-83 KASH domain in a membrane-bound, split-ubiquitin yeast two-hybrid system. However, the SUN domain was essential for UNC-84 function and UNC-83 localization in vivo. These data support the model that KASH and SUN proteins bridge the nuclear envelope, connecting the nuclear lamina to cytoskeletal components. This mechanism seems conserved across eukaryotes and is the first proposed mechanism to target proteins specifically to the outer nuclear membrane.
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Alvarado-Kristensson, Maria, and Catalina Ana Rosselló. "The Biology of the Nuclear Envelope and Its Implications in Cancer Biology." International Journal of Molecular Sciences 20, no. 10 (May 27, 2019): 2586. http://dx.doi.org/10.3390/ijms20102586.
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The formation of the nuclear envelope and the subsequent compartmentalization of the genome is a defining feature of eukaryotes. Traditionally, the nuclear envelope was purely viewed as a physical barrier to preserve genetic material in eukaryotic cells. However, in the last few decades, it has been revealed to be a critical cellular component in controlling gene expression and has been implicated in several human diseases. In cancer, the relevance of the cell nucleus was first reported in the mid-1800s when an altered nuclear morphology was observed in tumor cells. This review aims to give a current and comprehensive view of the role of the nuclear envelope on cancer first by recapitulating the changes of the nuclear envelope during cell division, second, by reviewing the role of the nuclear envelope in cell cycle regulation, signaling, and the regulation of the genome, and finally, by addressing the nuclear envelope link to cell migration and metastasis and its use in cancer prognosis.
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Ha, Mihyang, Ji-Young Kim, Myoung-Eun Han, Ga Hyun Kim, Si Young Park, Dae Cheon Jeong, Sae-Ock Oh, and Yun Hak Kim. "TMEM18: A Novel Prognostic Marker in Acute Myeloid Leukemia." Acta Haematologica 140, no. 2 (2018): 71–76. http://dx.doi.org/10.1159/000492742.
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Background: Certain nuclear envelope proteins are associated with important cancer cell characteristics, including migration and proliferation. Abnormal expression of and genetic changes in nuclear envelope proteins have been reported in acute myeloid leukemia (AML) patients. Transmembrane protein 18 (TMEM18), a nuclear envelope protein, is involved in neural stem cell migration and tumorigenicity. Methods: To examine the prognostic significance of TMEM18 in AML patients, we analyzed an AML cohort from The Cancer Genome Atlas (TCGA, n = 142). Results: Kaplan-Meier survival analysis revealed that TMEM18 overexpression was associated with a better AML prognosis with good discrimination (p = 0.019). Interestingly, this ability to predict the prognosis was significant in male AML patients, but not in female ones. C-index and area-under-the-curve analyses further supported this discriminative ability and multivariate analysis confirmed its prognostic significance (p = 0.00347). Correlation analysis revealed that TMEM18 had a statistically significant positive correlation with nuclear envelop protein 133 (NUP133), NUP35, NUP54, NUP62, and NUP88. Conclusion: Because the current AML prognostic factors do not take mRNA expression into consideration unlike other cancers, the development of mRNA-based prognostic factors would be beneficial for accurate prediction of the survival of AML patients. Therefore, TMEM18 gene is a potential biomarker for AML.
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Saunders, Cosmo A., Nathan J. Harris, Patrick T. Willey, Brian M. Woolums, Yuexia Wang, Alex J. McQuown, Amy Schoenhofen, et al. "TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement." Journal of Cell Biology 216, no. 3 (February 27, 2017): 657–74. http://dx.doi.org/10.1083/jcb.201507113.
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The nucleus is positioned toward the rear of most migratory cells. In fibroblasts and myoblasts polarizing for migration, retrograde actin flow moves the nucleus rearward, resulting in the orientation of the centrosome in the direction of migration. In this study, we report that the nuclear envelope–localized AAA+ (ATPase associated with various cellular activities) torsinA (TA) and its activator, the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1), are required for rearward nuclear movement during centrosome orientation in migrating fibroblasts. Both TA and LAP1 contributed to the assembly of transmembrane actin-associated nuclear (TAN) lines, which couple the nucleus to dorsal perinuclear actin cables undergoing retrograde flow. In addition, TA localized to TAN lines and was necessary for the proper mobility of EGFP-mini–nesprin-2G, a functional TAN line reporter construct, within the nuclear envelope. Furthermore, TA and LAP1 were indispensable for the retrograde flow of dorsal perinuclear actin cables, supporting the recently proposed function for the nucleus in spatially organizing actin flow and cytoplasmic polarity. Collectively, these results identify TA as a key regulator of actin-dependent rearward nuclear movement during centrosome orientation.
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Dufresne, L., I. Neant, J. St-Pierre, F. Dube, and P. Guerrier. "Effects of 6-dimethylaminopurine on microtubules and putative intermediate filaments in sea urchin embryos." Journal of Cell Science 99, no. 4 (August 1, 1991): 721–30. http://dx.doi.org/10.1242/jcs.99.4.721.
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The effects of 6-dimethylaminopurine (6-DMAP) (a putative phosphorylation inhibitor) on the state of assembly of microtubules and intermediate filaments have been studied during the first cell cycle of the sea urchin Strongylocentrotus droebachiensis. Changes in the spatial organization of cytoskeletal structures were studied by indirect immunofluorescence with anti-tubulin and anti-IFa antibodies. The rates and patterns of protein phosphorylation in control and treated eggs were also investigated. The transfer of fertilized eggs to 600 microM 6-DMAP within 4 min following insemination inhibits pronuclear migration and syngamy. This also prevents male pronuclear decondensation, while chromatin condensation and nuclear envelope breakdown do not occur in the female pronucleus. Immunolabeling with anti-tubulin antibodies reveals the presence of cortical microtubules as early as 15 min after fertilization in both control and treated eggs. However, no sperm astral microtubules could be detected in the treated eggs. At later stages, from syngamy (40 min) up to nuclear envelope breakdown (90 min), 6-DMAP affects neither cortical microtubule organization nor the state of chromatin condensation but it precludes nuclear envelope breakdown and entry into mitosis. Treatment of the fertilized eggs after nuclear envelope breakdown induces permanent chromosome decondensation and premature disappearance of the mitotic apparatus. This last event involves disruption of the spatial organization of both microtubules and putative intermediate filaments. Quantitative measurements of protein phosphorylation show that 6-DMAP efficiently and reversibly inhibits 32P incorporation into proteins. Qualitative analysis of the autoradiograms of 32P-labeled proteins separated by SDS-PAGE reveals that a major protein band, migrating with an apparent molecular weight of 31 × 10(3)Mr, is specifically dephosphorylated in eggs treated with 6-DMAP. This study suggests that protein phosphorylation is required for sperm aster microtubule growth and migration, but not for cortical microtubule polymerization. It also strengthens the hypothesis that, in sea urchin eggs, putative intermediate filaments are tightly associated with spindle microtubules. Finally, it confirms that inhibiting protein phosphorylation before nuclear envelope breakdown reversibly prevents the entry into mitosis.
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Islam, Md Ariful, Ho Jin Choi, Raju Dash, Syeda Ridita Sharif, Diyah Fatimah Oktaviani, Dae-Hyun Seog, and Il Soo Moon. "N-Acetyl-d-Glucosamine Kinase Interacts with NudC and Lis1 in Dynein Motor Complex and Promotes Cell Migration." International Journal of Molecular Sciences 22, no. 1 (December 24, 2020): 129. http://dx.doi.org/10.3390/ijms22010129.
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Recently, we showed that N-acetylglucosamine kinase (NAGK), an enzyme of amino sugar metabolism, interacts with dynein light chain roadblock type 1 (DYNLRB1) and promotes the functions of dynein motor. Here, we report that NAGK interacts with nuclear distribution protein C (NudC) and lissencephaly 1 (Lis1) in the dynein complex. Yeast two-hybrid assays, pull-down assays, immunocytochemistry, and proximity ligation assays revealed NAGK–NudC–Lis1–dynein complexes around nuclei, at the leading poles of migrating HEK293T cells, and at the tips of migratory processes of cultured rat neuroblast cells. The exogenous expression of red fluorescent protein (RFP)-tagged NAGK accelerated HEK293T cell migration during in vitro wound-healing assays and of neurons during in vitro neurosphere migration and in utero electroporation assays, whereas NAGK knockdown by short hairpin RNA (shRNA) delayed migration. Finally, a small NAGK peptide derived from the NudC interacting domain in in silico molecular docking analysis retarded the migrations of HEK293T and SH-SY5Y cells. These data indicate a functional interaction between NAGK and dynein–NudC–Lis1 complex at the nuclear envelope is required for the regulation of cell migration.
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Lee, Kenneth K., Daniel Starr, Merav Cohen, Jun Liu, Min Han, Katherine L. Wilson, and Yosef Gruenbaum. "Lamin-dependent Localization of UNC-84, A Protein Required for Nuclear Migration in Caenorhabditis elegans." Molecular Biology of the Cell 13, no. 3 (March 2002): 892–901. http://dx.doi.org/10.1091/mbc.01-06-0294.
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Mutations in the Caenorhabditis elegans unc-84 gene cause defects in nuclear migration and anchoring. We show that endogenous UNC-84 protein colocalizes with Ce-lamin at the nuclear envelope and that the envelope localization of UNC-84 requires Ce-lamin. We also show that during mitosis, UNC-84 remains at the nuclear periphery until late anaphase, similar to known inner nuclear membrane proteins. UNC-84 protein is first detected at the 26-cell stage and thereafter is present in most cells during development and in adults. UNC-84 is properly expressed in unc-83 andanc-1 lines, which have phenotypes similar tounc-84, suggesting that neither the expression nor nuclear envelope localization of UNC-84 depends on UNC-83 or ANC-1 proteins. The envelope localization of Ce-lamin, Ce-emerin, Ce-MAN1, and nucleoporins are unaffected by the loss of UNC-84. UNC-84 is not required for centrosome attachment to the nucleus because centrosomes are localized normally in unc-84 hyp7 cells despite a nuclear migration defect. Models for UNC-84 localization are discussed.
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Elacqua, Joshua J., Alexandra L. McGregor, and Jan Lammerding. "Automated analysis of cell migration and nuclear envelope rupture in confined environments." PLOS ONE 13, no. 4 (April 12, 2018): e0195664. http://dx.doi.org/10.1371/journal.pone.0195664.
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Fracchia, Andrea, Tal Asraf, Mali Salmon-Divon, and Gabi Gerlitz. "Increased Lamin B1 Levels Promote Cell Migration by Altering Perinuclear Actin Organization." Cells 9, no. 10 (September 24, 2020): 2161. http://dx.doi.org/10.3390/cells9102161.
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Cell migration requires reposition and reshaping of the cell nucleus. The nuclear lamina is highly important for migration of both primary and cancer cells. B-type lamins are important for proper migration of epicardial cells and neurons and increased lamin B to lamin A ratio accelerates cancer cell migration through confined spaces. Moreover, a positive association between lamin B1 levels and tumor formation and progression is found in various cancer types. Still, the molecular mechanism by which B-type lamins promote cell migration is not fully understood. To better understand this mechanism, we tested the effects of lamin B1 on perinuclear actin organization. Here we show that induction of melanoma cell migration leads to the formation of a cytosolic Linker of Nucleoskeleton and Cytoskeleton (LINC) complex-independent perinuclear actin rim, which has not been detected in migrating cells, yet. Significantly, increasing the levels of lamin B1 but not the levels of lamin A prevented perinuclear actin rim formation while accelerated the cellular migration rate. To interfere with the perinuclear actin rim, we generated a chimeric protein that is localized to the outer nuclear membrane and cleaves perinuclear actin filaments in a specific manner without disrupting other cytosolic actin filaments. Using this tool, we found that disruption of the perinuclear actin rim accelerated the cellular migration rate in a similar manner to lamin B1 over-expression. Taken together, our results suggest that increased lamin B1 levels can accelerate cell migration by inhibiting the association of the nuclear envelope with actin filaments that may reduce nuclear movement and deformability.
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Boudreau, Vincent, Richard Chen, Alan Edwards, Muhammad Sulaimain, and Paul S. Maddox. "PP2A-B55/SUR-6 collaborates with the nuclear lamina for centrosome separation during mitotic entry." Molecular Biology of the Cell 30, no. 7 (March 21, 2019): 876–86. http://dx.doi.org/10.1091/mbc.e18-10-0631.
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Across most sexually reproducing animals, centrosomes are provided to the oocyte through fertilization and must be positioned properly to establish the zygotic mitotic spindle. How centrosomes are positioned in space and time through the concerted action of key mitotic entry biochemical regulators, including protein phosphatase 2A (PP2A-B55/SUR-6), biophysical regulators, including dynein, and the nuclear lamina is unclear. Here, we uncover a role for PP2A-B55/SUR-6 in regulating centrosome separation. Mechanistically, PP2A-B55/SUR-6 regulates nuclear size before mitotic entry, in turn affecting nuclear envelope–based dynein density and motor capacity. Computational simulations predicted the requirement of PP2A-B55/SUR-6 regulation of nuclear size and nuclear-envelope dynein density for proper centrosome separation. Conversely, compromising nuclear lamina integrity led to centrosome detachment from the nuclear envelope and migration defects. Removal of PP2A-B55/SUR-6 and the nuclear lamina simultaneously further disrupted centrosome separation, leading to unseparated centrosome pairs dissociated from the nuclear envelope. Taking these combined results into consideration, we propose a model in which centrosomes migrate and are positioned through the concerted action of PP2A-B55/SUR-6–regulated nuclear envelope–based dynein pulling forces and centrosome–nuclear envelope tethering. Our results add critical precision to models of centrosome separation relative to the nucleus during spindle formation in cell division.
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Malone, C. J., W. D. Fixsen, H. R. Horvitz, and M. Han. "UNC-84 localizes to the nuclear envelope and is required for nuclear migration and anchoring during C. elegans development." Development 126, no. 14 (July 15, 1999): 3171–81. http://dx.doi.org/10.1242/dev.126.14.3171.
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Nuclear migrations are essential for metazoan development. Two nuclear migrations that occur during C. elegans development require the function of the unc-84 gene. unc-84 mutants are also defective in the anchoring of nuclei within the hypodermal syncytium and in the migrations of the two distal tip cells of the gonad. Complementation analyses of 17 unc-84 alleles defined two genetically separable functions. Both functions are required for nuclear and distal tip cell migrations, but only one is required for nuclear anchorage. The DNA lesions associated with these 17 mutations indicate that the two genetically defined functions correspond to two distinct regions of the UNC-84 protein. The UNC-84 protein has a predicted transmembrane domain and a C-terminal region with similarity to the S. pombe spindle pole body protein Sad1 and to two predicted mammalian proteins. Analysis of a green fluorescent protein reporter indicated that UNC-84 is widely expressed and localized to the nuclear envelope. We propose that UNC-84 functions to facilitate a nuclear-centrosomal interaction required for nuclear migration and anchorage.
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Figueroa, Ricardo A., Santhosh Gudise, and Einar Hallberg. "Microtubule-associated nuclear envelope proteins in interphase and mitosis." Biochemical Society Transactions 39, no. 6 (November 21, 2011): 1786–89. http://dx.doi.org/10.1042/bst20110680.
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The LINC (linker of nucleoskeleton and cytoskeleton) complex forms a transcisternal bridge across the NE (nuclear envelope) that connects the cytoskeleton with the nuclear interior. This enables some proteins of the NE to communicate with the centrosome and the microtubule cytoskeleton. The position of the centrosome relative to the NE is of vital importance for many cell functions, such as cell migration and division, and centrosomal dislocation is a frequent phenotype in laminopathic disorders. Also in mitosis, a small group of transmembrane NE proteins associate with microtubules when they concentrate in a specific membrane domain associated with the mitotic spindle. The present review discusses structural and functional aspects of microtubule association with NE proteins and how this association may be maintained over the cell cycle.
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Mestres, Ivan, Judith Houtman, Federico Calegari, and Tomohisa Toda. "A Nuclear Belt Fastens on Neural Cell Fate." Cells 11, no. 11 (May 27, 2022): 1761. http://dx.doi.org/10.3390/cells11111761.
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Successful embryonic and adult neurogenesis require proliferating neural stem and progenitor cells that are intrinsically and extrinsically guided into a neuronal fate. In turn, migration of new-born neurons underlies the complex cytoarchitecture of the brain. Proliferation and migration are therefore essential for brain development, homeostasis and function in adulthood. Among several tightly regulated processes involved in brain formation and function, recent evidence points to the nuclear envelope (NE) and NE-associated components as critical new contributors. Classically, the NE was thought to merely represent a barrier mediating selective exchange between the cytoplasm and nucleoplasm. However, research over the past two decades has highlighted more sophisticated and diverse roles for NE components in progenitor fate choice and migration of their progeny by tuning gene expression via interactions with chromatin, transcription factors and epigenetic factors. Defects in NE components lead to neurodevelopmental impairments, whereas age-related changes in NE components are proposed to influence neurodegenerative diseases. Thus, understanding the roles of NE components in brain development, maintenance and aging is likely to reveal new pathophysiological mechanisms for intervention. Here, we review recent findings for the previously underrepresented contribution of the NE in neuronal commitment and migration, and envision future avenues for investigation.
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Kirchenbauer, Marisa, and Dimitris Liakopoulos. "An auxiliary, membrane-based mechanism for nuclear migration in budding yeast." Molecular Biology of the Cell 24, no. 9 (May 2013): 1434–43. http://dx.doi.org/10.1091/mbc.e12-08-0602.
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How nuclear shape correlates with nuclear movements during the cell cycle is poorly understood. We investigated changes in nuclear morphology during nuclear migration in budding yeast. In preanaphase cells, nuclear protrusions (nucleopodia [NP]) extend into the bud, preceding insertion of chromosomes into the bud neck. Surprisingly, formation of nucleopodia did not depend on the established nuclear migration pathways. We show that generation and maintenance of NP requires nuclear membrane expansion, actin, and the exocyst complex. Exocyst mutations cause nuclear positioning defects and display genetic interactions with mutations that deactivate astral microtubule-dependent nuclear migration. Cells that cannot perform DNA replication also fail to form nucleopodia. We propose that nuclear membrane expansion, DNA replication, and exocyst-dependent anchoring of the nuclear envelope to the bud affect nuclear morphology and facilitate correct positioning of nucleus and chromosomes relative to the cleavage apparatus.
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Irianto, Jerome, Charlotte R. Pfeifer, Rachel R. Bennett, Yuntao Xia, Irena L. Ivanovska, Andrea J. Liu, Roger A. Greenberg, and Dennis E. Discher. "Nuclear constriction segregates mobile nuclear proteins away from chromatin." Molecular Biology of the Cell 27, no. 25 (December 15, 2016): 4011–20. http://dx.doi.org/10.1091/mbc.e16-06-0428.
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As a cell squeezes its nucleus through adjacent tissue, penetrates a basement membrane, or enters a small blood capillary, chromatin density and nuclear factors could in principle be physically perturbed. Here, in cancer cell migration through rigid micropores and in passive pulling into micropipettes, local compaction of chromatin is observed coincident with depletion of mobile factors. Heterochromatin/euchromatin was previously estimated from molecular mobility measurements to occupy a volume fraction f of roughly two-thirds of the nuclear volume, but based on the relative intensity of DNA and histones in several cancer cell lines drawn into narrow constrictions, f can easily increase locally to nearly 100%. By contrast, mobile proteins in the nucleus, including a dozen that function as DNA repair proteins (e.g., BRCA1, 53BP1) or nucleases (e.g., Cas9, FokI), are depleted within the constriction, approaching 0%. Such losses—compounded by the occasional rupture of the nuclear envelope—can have important functional consequences. Studies of a nuclease that targets a locus in chromosome-1 indeed show that constricted migration delays DNA damage.
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Ketema, Mirjam, Maaike Kreft, Pablo Secades, Hans Janssen, and Arnoud Sonnenberg. "Nesprin-3 connects plectin and vimentin to the nuclear envelope of Sertoli cells but is not required for Sertoli cell function in spermatogenesis." Molecular Biology of the Cell 24, no. 15 (August 2013): 2454–66. http://dx.doi.org/10.1091/mbc.e13-02-0100.
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Nesprin-3 is a nuclear envelope protein that connects the nucleus to intermediate filaments by interacting with plectin. To investigate the role of nesprin-3 in the perinuclear localization of plectin, we generated nesprin-3–knockout mice and examined the effects of nesprin-3 deficiency in different cell types and tissues. Nesprin-3 and plectin are coexpressed in a variety of tissues, including peripheral nerve and muscle. The expression level of nesprin-3 in skeletal muscle is very low and decreases during myoblast differentiation in vitro. Of interest, plectin was concentrated at the nuclear envelope in only a few cell types. This was most prominent in Sertoli cells of the testis, in which nesprin-3 is required for the localization of both plectin and vimentin at the nuclear perimeter. Testicular morphology and the position of the nucleus in Sertoli cells were normal, however, in the nesprin-3–knockout mice and the mice were fertile. Furthermore, nesprin-3 was not required for the polarization and migration of mouse embryonic fibroblasts. Thus, although nesprin-3 is critical for the localization of plectin to the nuclear perimeter of Sertoli cells, the resulting link between the nuclear envelope and the intermediate filament system seems to be dispensable for normal testicular morphology and spermatogenesis.
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Castro, Domingos, Vanessa Nunes, Joana T. Lima, Jorge G. Ferreira, and Paulo Aguiar. "Trackosome: a computational toolbox to study the spatiotemporal dynamics of centrosomes, nuclear envelope and cellular membrane." Journal of Cell Science 133, no. 24 (November 16, 2020): jcs252254. http://dx.doi.org/10.1242/jcs.252254.
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ABSTRACTDuring the initial stages of mitosis, multiple mechanisms drive centrosome separation and positioning. How they are coordinated to promote centrosome migration to opposite sides of the nucleus remains unclear. Here, we present Trackosome, an open-source image analysis software for tracking centrosomes and reconstructing nuclear and cellular membranes, based on volumetric live-imaging data. The toolbox runs in MATLAB and provides a graphical user interface for easy access to the tracking and analysis algorithms. It provides detailed quantification of the spatiotemporal relationships between centrosomes, nuclear envelope and cellular membrane, and can also be used to measure the dynamic fluctuations of the nuclear envelope. These fluctuations are important because they are related to the mechanical forces exerted on the nucleus by its adjacent cytoskeletal structures. Unlike previous algorithms based on circular or elliptical approximations, Trackosome measures membrane movement in a model-free condition, making it viable for irregularly shaped nuclei. Using Trackosome, we demonstrate significant correlations between the movements of the centrosomes, and identify specific oscillation modes of the nuclear envelope. Overall, Trackosome is a powerful tool that can be used to help unravel new elements in the spatiotemporal dynamics of subcellular structures.
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Raab, M., M. Gentili, H. de Belly, H. R. Thiam, P. Vargas, A. J. Jimenez, F. Lautenschlaeger, et al. "ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death." Science 352, no. 6283 (March 24, 2016): 359–62. http://dx.doi.org/10.1126/science.aad7611.
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Maciejowski, John, and Emily M. Hatch. "Nuclear Membrane Rupture and Its Consequences." Annual Review of Cell and Developmental Biology 36, no. 1 (October 6, 2020): 85–114. http://dx.doi.org/10.1146/annurev-cellbio-020520-120627.
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The nuclear envelope is often depicted as a static barrier that regulates access between the nucleus and the cytosol. However, recent research has identified many conditions in cultured cells and in vivo in which nuclear membrane ruptures cause the loss of nuclear compartmentalization. These conditions include some that are commonly associated with human disease, such as migration of cancer cells through small spaces and expression of nuclear lamin disease mutations in both cultured cells and tissues undergoing nuclear migration. Nuclear membrane ruptures are rapidly repaired in the nucleus but persist in nuclear compartments that form around missegregated chromosomes called micronuclei. This review summarizes what is known about the mechanisms of nuclear membrane rupture and repair in both the main nucleus and micronuclei, and highlights recent work connecting the loss of nuclear integrity to genome instability and innate immune signaling. These connections link nuclear membrane rupture to complex chromosome alterations, tumorigenesis, and laminopathy etiologies.
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Zhou, Lixin, and Nelly Panté. "The nucleoporin Nup153 maintains nuclear envelope architecture and is required for cell migration in tumor cells." FEBS Letters 584, no. 14 (May 24, 2010): 3013–20. http://dx.doi.org/10.1016/j.febslet.2010.05.038.
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Turgay, Yagmur, Lysie Champion, Csaba Balazs, Michael Held, Alberto Toso, Daniel W. Gerlich, Patrick Meraldi, and Ulrike Kutay. "SUN proteins facilitate the removal of membranes from chromatin during nuclear envelope breakdown." Journal of Cell Biology 204, no. 7 (March 24, 2014): 1099–109. http://dx.doi.org/10.1083/jcb.201310116.
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SUN proteins reside in the inner nuclear membrane and form complexes with KASH proteins of the outer nuclear membrane that connect the nuclear envelope (NE) to the cytoskeleton. These complexes have well-established functions in nuclear anchorage and migration in interphase, but little is known about their involvement in mitotic processes. Our analysis demonstrates that simultaneous depletion of human SUN1 and SUN2 delayed removal of membranes from chromatin during NE breakdown (NEBD) and impaired the formation of prophase NE invaginations (PNEIs), similar to microtubule depolymerization or down-regulation of the dynein cofactors NudE/EL. In addition, overexpression of dominant-negative SUN and KASH constructs reduced the occurrence of PNEI, indicating a requirement for functional SUN–KASH complexes in NE remodeling. Codepletion of SUN1/2 slowed cell proliferation and resulted in an accumulation of morphologically defective and disoriented mitotic spindles. Quantification of mitotic timing revealed a delay between NEBD and chromatin separation, indicating a role of SUN proteins in bipolar spindle assembly and mitotic progression.
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Tran, Joseph R., Xiaobin Zheng, and Yixian Zheng. "Lamin-B1 contributes to the proper timing of epicardial cell migration and function during embryonic heart development." Molecular Biology of the Cell 27, no. 25 (December 15, 2016): 3956–63. http://dx.doi.org/10.1091/mbc.e16-06-0462.
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Lamin proteins form a meshwork beneath the nuclear envelope and contribute to many different cellular processes. Mutations in lamins cause defective organogenesis in mouse models and human diseases that affect adipose tissue, brain, skeletal muscle, and the heart. In vitro cell culture studies have shown that lamins help maintain nuclear shape and facilitate cell migration. However, whether these defects contribute to improper tissue building in vivo requires further clarification. By studying the heart epicardium during embryogenesis, we show that Lb1-null epicardial cells exhibit in vivo and in vitro migratory delay. Transcriptome analyses of these cells suggest that Lb1 influences the expression of cell adhesion genes, which could affect cell migration during epicardium development. These epicardial defects are consistent with incomplete development of both vascular smooth muscle and compact myocardium at later developmental stages in Lb1-null embryos. Further, we found that Lb1-null epicardial cells have a delayed nuclear morphology change in vivo, suggesting that Lb1 facilitates morphological changes associated with migration. These findings suggest that Lb1 contributes to nuclear shape maintenance and migration of epicardial cells and highlights the use of these cells for in vitro and in vivo study of these classic cell biological phenomena.
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Frye, Keyada, Fioranna Renda, Maria Fomicheva, Xiaodong Zhu, Lisa Gong, Alexey Khodjakov, and Irina Kaverina. "Cell Cycle-Dependent Dynamics of the Golgi-Centrosome Association in Motile Cells." Cells 9, no. 5 (April 25, 2020): 1069. http://dx.doi.org/10.3390/cells9051069.
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Here, we characterize spatial distribution of the Golgi complex in human cells. In contrast to the prevailing view that the Golgi compactly surrounds the centrosome throughout interphase, we observe characteristic differences in the morphology of Golgi ribbons and their association with the centrosome during various periods of the cell cycle. The compact Golgi complex is typical in G1; during S-phase, Golgi ribbons lose their association with the centrosome and extend along the nuclear envelope to largely encircle the nucleus in G2. Interestingly, pre-mitotic separation of duplicated centrosomes always occurs after dissociation from the Golgi. Shortly before the nuclear envelope breakdown, scattered Golgi ribbons reassociate with the separated centrosomes restoring two compact Golgi complexes. Transitions between the compact and distributed Golgi morphologies are microtubule-dependent. However, they occur even in the absence of centrosomes, which implies that Golgi reorganization is not driven by the centrosomal microtubule asters. Cells with different Golgi morphology exhibit distinct differences in the directional persistence and velocity of migration. These data suggest that changes in the radial distribution of the Golgi around the nucleus define the extent of cell polarization and regulate cell motility in a cell cycle-dependent manner.
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Gallardo, Paola, Ramón R. Barrales, Rafael R. Daga, and Silvia Salas-Pino. "Nuclear Mechanics in the Fission Yeast." Cells 8, no. 10 (October 20, 2019): 1285. http://dx.doi.org/10.3390/cells8101285.
Full textAbstract:
In eukaryotic cells, the organization of the genome within the nucleus requires the nuclear envelope (NE) and its associated proteins. The nucleus is subjected to mechanical forces produced by the cytoskeleton. The physical properties of the NE and the linkage of chromatin in compacted conformation at sites of cytoskeleton contacts seem to be key for withstanding nuclear mechanical stress. Mechanical perturbations of the nucleus normally occur during nuclear positioning and migration. In addition, cell contraction or expansion occurring for instance during cell migration or upon changes in osmotic conditions also result innuclear mechanical stress. Recent studies in Schizosaccharomyces pombe (fission yeast) have revealed unexpected functions of cytoplasmic microtubules in nuclear architecture and chromosome behavior, and have pointed to NE-chromatin tethers as protective elements during nuclear mechanics. Here, we review and discuss how fission yeast cells can be used to understand principles underlying the dynamic interplay between genome organization and function and the effect of forces applied to the nucleus by the microtubule cytoskeleton.
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Pfeifer, Charlotte R., Manasvita Vashisth, Yuntao Xia, and Dennis E. Discher. "Nuclear failure, DNA damage, and cell cycle disruption after migration through small pores: a brief review." Essays in Biochemistry 63, no. 5 (July 31, 2019): 569–77. http://dx.doi.org/10.1042/ebc20190007.
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Abstract In many contexts of development, regeneration, or disease such as cancer, a cell squeezes through a dense tissue or a basement membrane, constricting its nucleus. Here, we describe how the severity of nuclear deformation depends on a nucleus’ mechanical properties that are mostly determined by the density of chromatin and by the nuclear lamina. We explain how constriction-induced nuclear deformation affects nuclear contents by causing (i) local density changes in chromatin and (ii) rupture of the nuclear lamina and envelope. Both processes mislocalize diffusible nuclear factors including key DNA repair and regulatory proteins. Importantly, these effects of constricted migration are accompanied by excess DNA damage, marked by phosphorylated histone γH2AX in fixed cells. Rupture has a number of downstream consequences that include a delayed cell cycle—consistent with a damage checkpoint—and modulation of differentiation, both of which are expected to affect migration-dependent processes ranging from wound healing to tumorigenic invasion.
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Shan, X., Z. Xue, G. Euskirchen, and T. Melese. "NNF1 is an essential yeast gene required for proper spindle orientation, nucleolar and nuclear envelope structure and mRNA export." Journal of Cell Science 110, no. 14 (July 15, 1997): 1615–24. http://dx.doi.org/10.1242/jcs.110.14.1615.
Full textAbstract:
The nuclear envelope is central to nuclear structure and function. It plays a role in maintaining nuclear shape, allowing the exchange of macromolecules between the nucleus and the cytoplasm (via the nuclear pore complexes), and providing attachment sites for microtubules during chromosome segregation and nuclear migration (via the spindle pole body). We have isolated an essential yeast gene, NNF1 that is required for a number of nuclear functions. Cells depleted of Nnf1p or containing a temperature-sensitive nnf1 mutation have elongated microtubules and become bi- and multinucleate. They also have a fragmented nucleolous and accumulate poly(A)+ RNA inside the nucleus. A similar constellation of phenotypes has been reported in cells carrying mutations in a number of nuclear pore proteins, components of the Ran GTPase cycle, and the nuclear localization sequence receptor protein. Our results suggest that Nnf1p plays a role in a number of nuclear functions.
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Liddane, Alexandra G., and James M. Holaska. "The Role of Emerin in Cancer Progression and Metastasis." International Journal of Molecular Sciences 22, no. 20 (October 19, 2021): 11289. http://dx.doi.org/10.3390/ijms222011289.
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It is commonly recognized in the field that cancer cells exhibit changes in the size and shape of their nuclei. These features often serve as important biomarkers in the diagnosis and prognosis of cancer patients. Nuclear size can significantly impact cell migration due to its incredibly large size. Nuclear structural changes are predicted to regulate cancer cell migration. Nuclear abnormalities are common across a vast spectrum of cancer types, regardless of tissue source, mutational spectrum, and signaling dependencies. The pervasiveness of nuclear alterations suggests that changes in nuclear structure may be crucially linked to the transformation process. The factors driving these nuclear abnormalities, and the functional consequences, are not completely understood. Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamina proteins, including emerin, is found in many cancers and this expression is correlated with better clinical outcomes. A model is emerging whereby emerin, as well as other nuclear lamina proteins, binding to the nucleoskeleton regulates the nuclear structure to impact metastasis. In this model, emerin and lamins play a central role in metastatic transformation, since decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. Herein, we discuss the cellular functions of nuclear lamina proteins, with a particular focus on emerin, and how these functions impact cancer progression and metastasis.
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BROWN, R. C., and B. E. LEMMON. "Pollen development in orchids." Journal of Cell Science 99, no. 2 (June 1, 1991): 273–81. http://dx.doi.org/10.1242/jcs.99.2.273.
Full textAbstract:
Cytoplasmic preparation for the unequal first mitosis in non-vacuolate pollen of moth orchids (Phalaenopsis) includes reorganization of the microtubular cytoskeleton and nuclear migration. Following meiotic cytokinesis, both microtubules and F-actin are unpolarized in microspores of persistent tetrads. Microtubules radiate from the centrally located nucleus and F-actin forms a reticulate pattern in the cytoplasm. Polarization of the microspores is marked by a dramatic reorganization of microtubules while the pattern of F-actin remains unchanged. We describe a novel system of microtubules at the generative pole (GPMS), which forms a polar structure structure at the distal surface and marks the path of nuclear migration prior to pollen mitosis. The GPMS consists of numerous microtubules that extend between the plasma membrane and nuclear envelope. The nucleus becomes displaced toward the generative pole and flattened in association with microtubules of the GPMS. Initiation of the GPMS is marked by a localized proliferation of ER and clearing of large organelles from the generative pole.
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Gauthier, Benoit R., Petra I. Lorenzo, and Valentine Comaills. "Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?" Cancers 14, no. 1 (December 24, 2021): 83. http://dx.doi.org/10.3390/cancers14010083.
Full textAbstract:
During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.
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Bogerd, A. M., J. A. Hoffman, D. C. Amberg, G. R. Fink, and L. I. Davis. "nup1 mutants exhibit pleiotropic defects in nuclear pore complex function." Journal of Cell Biology 127, no. 2 (October 15, 1994): 319–32. http://dx.doi.org/10.1083/jcb.127.2.319.
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The NUP1 gene of Saccharomyces cerevisiae encodes one member of a family of nuclear pore complex proteins (nucleoporins) conserved from yeast to vertebrates. We have used mutational analysis to investigate the function of Nup1p. Deletion of either the amino- or carboxy-terminal domain confers a lethal phenotype, but partial truncations at either end affect growth to varying extents. Amino-terminal truncation causes mislocalization and degradation of the mutant protein, suggesting that this domain is required for targeting Nup1p to the nuclear pore complex. Carboxy-terminal mutants are stable but do not have wild-type function, and confer a temperature sensitive phenotype. Both import of nuclear proteins and export of poly(A) RNA are defective at the nonpermissive temperature. In addition, nup1 mutant cells become multinucleate at all temperatures, a phenotype suggestive of a defect in nuclear migration. Tubulin staining revealed that the mitotic spindle appears to be oriented randomly with respect to the bud, in spite of the presence of apparently normal cytoplasmic microtubules connecting one spindle pole body to the bud tip. EM analysis showed that the nuclear envelope forms long projections extending into the cytoplasm, which appear to have detached from the bulk of the nucleus. Our results suggest that Nup1p may be required to retain the structural integrity between the nuclear envelope and an underlying nuclear scaffold, and that this connection is required to allow reorientation of the nucleus in response to cytoskeletal forces.
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Hebbar, Sachin, Mariano T. Mesngon, Aimee M. Guillotte, Bhavim Desai, Ramses Ayala, and Deanna S. Smith. "Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells." Journal of Cell Biology 182, no. 6 (September 22, 2008): 1063–71. http://dx.doi.org/10.1083/jcb.200803071.
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Lis1 and Ndel1 are essential for animal development. They interact directly with one another and with cytoplasmic dynein. The developing brain is especially sensitive to reduced Lis1 or Ndel1 levels, as both proteins influence spindle orientation, neural cell fate decisions, and neuronal migration. We report here that Lis1 and Ndel1 reduction in a mitotic cell line impairs prophase nuclear envelope (NE) invagination (PNEI). This dynein-dependent process facilitates NE breakdown (NEBD) and occurs before the establishment of the bipolar spindle. Ndel1 phosphorylation is important for this function, regulating binding to both Lis1 and dynein. Prophase cells in the ventricular zone (VZ) of embryonic day 13.5 Lis1+/− mouse brains show reduced PNEI, and the ratio of prophase to prometaphase cells is increased, suggesting an NEBD delay. Moreover, prophase cells in the VZ contain elevated levels of Ndel1 phosphorylated at a key cdk5 site. Our data suggest that a delay in NEBD in the VZ could contribute to developmental defects associated with Lis1–Ndel1 disruption.
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McHugh, Brian, Sue A. Krause, Bin Yu, Anne-Marie Deans, Sarah Heasman, Paul McLaughlin, and Margarete M. S. Heck. "Invadolysin." Journal of Cell Biology 167, no. 4 (November 22, 2004): 673–86. http://dx.doi.org/10.1083/jcb.200405155.
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The cell cycle is widely known to be regulated by networks of phosphorylation and ubiquitin-directed proteolysis. Here, we describe IX-14/invadolysin, a novel metalloprotease present only in metazoa, whose activity appears to be essential for mitotic progression. Mitotic neuroblasts of Drosophila melanogaster IX-14 mutant larvae exhibit increased levels of nuclear envelope proteins, monopolar and asymmetric spindles, and chromosomes that appear hypercondensed in length with a surrounding halo of loosely condensed chromatin. Zymography reveals that a protease activity, present in wild-type larval brains, is missing from homozygous tissue, and we show that IX-14/invadolysin cleaves lamin in vitro. The IX-14/invadolysin protein is predominantly found in cytoplasmic structures resembling invadopodia in fly and human cells, but is dramatically relocalized to the leading edge of migrating cells. Strikingly, we find that the directed migration of germ cells is affected in Drosophila IX-14 mutant embryos. Thus, invadolysin identifies a new family of conserved metalloproteases whose activity appears to be essential for the coordination of mitotic progression, but which also plays an unexpected role in cell migration.
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Stick, R., B. Angres, C. F. Lehner, and E. A. Nigg. "The fates of chicken nuclear lamin proteins during mitosis: evidence for a reversible redistribution of lamin B2 between inner nuclear membrane and elements of the endoplasmic reticulum." Journal of Cell Biology 107, no. 2 (August 1, 1988): 397–406. http://dx.doi.org/10.1083/jcb.107.2.397.
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In chicken, three structurally distinct nuclear lamin proteins have been described. According to their migration on two-dimensional gels, these proteins have been designated as lamins A, B1, and B2. To investigate the functional relationship between chicken lamins and their mammalian counterparts, we have examined here the state of individual chicken lamin proteins during mitosis. Current models proposing functional specializations of mammalian lamin subtypes are in fact largely based on the observation that during mitosis mammalian lamin B remains associated with membrane vesicles, whereas lamins A and C become freely soluble. Cell fractionation experiments combined with immunoblotting show that during mitosis both chicken lamins B1 and B2 remain associated with membranes, whereas lamin A exists in a soluble form. In situ immunoelectron microscopy carried out on mitotic cells also reveals membrane association of lamin B2, whereas the distribution of lamin A is random. From these results we conclude that both chicken lamins B1 and B2 may functionally resemble mammalian lamin B. Interestingly, immunolabeling of mitotic cells revealed an association of lamin B2 with extended membrane cisternae that resembled elements of the endoplasmic reticulum. Quantitatively, we found that all large endoplasmic reticulum-like membranes present in metaphase cells were decorated with lamin B2-specific antibodies. Given that labeling of these mitotic membranes was lower than labeling of interphase nuclear envelopes, it appears likely that during mitotic disassembly and reassembly of the nuclear envelope lamin B2 may reversibly distribute between the inner nuclear membrane and the endoplasmic reticulum.
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Hah, Jungwon, and Dong-Hwee Kim. "Deciphering Nuclear Mechanobiology in Laminopathy." Cells 8, no. 3 (March 11, 2019): 231. http://dx.doi.org/10.3390/cells8030231.
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Extracellular mechanical stimuli are translated into biochemical signals inside the cell via mechanotransduction. The nucleus plays a critical role in mechanoregulation, which encompasses mechanosensing and mechanotransduction. The nuclear lamina underlying the inner nuclear membrane not only maintains the structural integrity, but also connects the cytoskeleton to the nuclear envelope. Lamin mutations, therefore, dysregulate the nuclear response, resulting in abnormal mechanoregulations, and ultimately, disease progression. Impaired mechanoregulations even induce malfunction in nuclear positioning, cell migration, mechanosensation, as well as differentiation. To know how to overcome laminopathies, we need to understand the mechanisms of laminopathies in a mechanobiological way. Recently, emerging studies have demonstrated the varying defects from lamin mutation in cellular homeostasis within mechanical surroundings. Therefore, this review summarizes recent findings highlighting the role of lamins, the architecture of nuclear lamina, and their disease relevance in the context of nuclear mechanobiology. We will also provide an overview of the differentiation of cellular mechanics in laminopathy.
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Lele, Tanmay P., Richard B. Dickinson, and Gregg G. Gundersen. "Mechanical principles of nuclear shaping and positioning." Journal of Cell Biology 217, no. 10 (September 7, 2018): 3330–42. http://dx.doi.org/10.1083/jcb.201804052.
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Positioning and shaping the nucleus represents a mechanical challenge for the migrating cell because of its large size and resistance to deformation. Cells shape and position the nucleus by transmitting forces from the cytoskeleton onto the nuclear surface. This force transfer can occur through specialized linkages between the nuclear envelope and the cytoskeleton. In response, the nucleus can deform and/or it can move. Nuclear movement will occur when there is a net differential in mechanical force across the nucleus, while nuclear deformation will occur when mechanical forces overcome the mechanical resistance of the various structures that comprise the nucleus. In this perspective, we review current literature on the sources and magnitude of cellular forces exerted on the nucleus, the nuclear envelope proteins involved in transferring cellular forces, and the contribution of different nuclear structural components to the mechanical response of the nucleus to these forces.
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Goto, Chieko, Kentaro Tamura, Satsuki Nishimaki, Daisuke Maruyama, and Ikuko Hara-Nishimura. "The nuclear envelope protein KAKU4 determines the migration order of the vegetative nucleus and sperm cells in pollen tubes." Journal of Experimental Botany 71, no. 20 (August 10, 2020): 6273–81. http://dx.doi.org/10.1093/jxb/eraa367.
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Abstract A putative component protein of the nuclear lamina, KAKU4, modulates nuclear morphology in Arabidopsis thaliana seedlings, but its physiological significance is unknown. KAKU4 was highly expressed in mature pollen grains, each of which has a vegetative cell and two sperm cells. KAKU4 protein was highly abundant on the envelopes of vegetative nuclei and less abundant on the envelopes of sperm cell nuclei in pollen grains and elongating pollen tubes. Vegetative nuclei are irregularly shaped in wild-type pollen. However, KAKU4 deficiency caused them to become more spherical. After a pollen grain germinates, the vegetative nuclei and sperm cells enter and move along the pollen tube. In the wild type, the vegetative nucleus preceded the sperm cell nuclei in >90% of the pollen tubes, whereas, in kaku4 mutants, the vegetative nucleus preceded the sperm cell nuclei in only about half of the pollen tubes. kaku4 pollen was less competitive for fertilization than wild-type pollen after pollination. These results led us to hypothesize that the nuclear shape in vegetative cells of pollen grains affects the orderly migration of the vegetative nucleus and sperm cells in pollen tubes.
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Morgan, Joshua T., Emily R. Pfeiffer, Twanda L. Thirkill, Priyadarsini Kumar, Gordon Peng, Heidi N. Fridolfsson, Gordon C. Douglas, Daniel A. Starr, and Abdul I. Barakat. "Nesprin-3 regulates endothelial cell morphology, perinuclear cytoskeletal architecture, and flow-induced polarization." Molecular Biology of the Cell 22, no. 22 (November 15, 2011): 4324–34. http://dx.doi.org/10.1091/mbc.e11-04-0287.
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Changes in blood flow regulate gene expression and protein synthesis in vascular endothelial cells, and this regulation is involved in the development of atherosclerosis. How mechanical stimuli are transmitted from the endothelial luminal surface to the nucleus is incompletely understood. The linker of nucleus and cytoskeleton (LINC) complexes have been proposed as part of a continuous physical link between the plasma membrane and subnuclear structures. LINC proteins nesprin-1, -2, and -4 have been shown to mediate nuclear positioning via microtubule motors and actin. Although nesprin-3 connects intermediate filaments to the nucleus, no functional consequences of nesprin-3 mutations on cellular processes have been described. Here we show that nesprin-3 is robustly expressed in human aortic endothelial cells (HAECs) and localizes to the nuclear envelope. Nesprin-3 regulates HAEC morphology, with nesprin-3 knockdown inducing prominent cellular elongation. Nesprin-3 also organizes perinuclear cytoskeletal organization and is required to attach the centrosome to the nuclear envelope. Finally, nesprin-3 is required for flow-induced polarization of the centrosome and flow-induced migration in HAECs. These results represent the most complete description to date of nesprin-3 function and suggest that nesprin-3 regulates vascular endothelial cell shape, perinuclear cytoskeletal architecture, and important aspects of flow-mediated mechanotransduction.
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Burke, Brian. "Chain reaction: LINC complexes and nuclear positioning." F1000Research 8 (January 31, 2019): 136. http://dx.doi.org/10.12688/f1000research.16877.1.
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Nuclear positioning plays an essential role in defining cell architecture and behaviour in both development and disease, and nuclear location frequently adjusts according to internal and external cues. For instance, during periods of migration in many cell types, the nucleus may be actively repositioned behind the microtubule-organising centre. Nuclear movement, for the most part, is dependent upon coupling of the cytoskeleton to the nuclear periphery. This is accomplished largely through SUN and KASH domain proteins, which together assemble to form LINC (linker of the nucleoskeleton and cytoskeleton) complexes spanning the nuclear envelope. SUN proteins of the inner nuclear membrane provide a connection to nuclear structures while acting as a tether for outer nuclear membrane KASH proteins. The latter contain binding sites for diverse cytoskeletal components. Recent publications highlight new aspects of LINC complex regulation revealing that the interplay between SUN and KASH partners can strongly influence how the nucleus functionally engages with different branches of the cytoskeleton.
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Baffet, Alexandre D., Daniel J. Hu, and Richard B. Vallee. "Cdk1 Activates Pre-mitotic Nuclear Envelope Dynein Recruitment and Apical Nuclear Migration in Neural Stem Cells." Developmental Cell 33, no. 6 (June 2015): 703–16. http://dx.doi.org/10.1016/j.devcel.2015.04.022.
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Song, Xiaoyue, Ruhong Li, Gang Liu, Lihua Huang, Peng Li, Wanjiang Feng, Qiujie Gao, and Xiaowei Xing. "Nuclear Membrane Protein SUN5 Is Highly Expressed and Promotes Proliferation and Migration in Colorectal Cancer by Regulating the ERK Pathway." Cancers 14, no. 21 (October 31, 2022): 5368. http://dx.doi.org/10.3390/cancers14215368.
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SUN5 was first identified as a nuclear envelope protein involved in spermatocyte division. We found that SUN5 was highly expressed in some cancers, but its function and mechanism in cancer development remain unclear. In the present study, we demonstrated that SUN5 was highly expressed in colorectal cancer (CRC) tissues and cells, as indicated by bioinformatics analysis, and SUN5 promoted cell proliferation and migration in vitro. Moreover, the overexpression of SUN5 upregulated phosphorylated ERK1/2 (pERK1/2), whereas the knockdown of SUN5 yielded the opposite results. PD0325901 decreased the level of pERK1/2 to inhibit cell proliferation and migration, which was partially reversed by SUN5 overexpression, indicating that drug resistance existed in patients with high SUN5 expression. The xenograft transplantation experiment showed that SUN5 accelerated tumor formation in vivo. Furthermore, we found that SUN5 regulated the ERK pathway via Nesprin2 mediation and promoted the nuclear translocation of pERK1/2 by interacting with Nup93. Thus, these findings indicated that highly expressed SUN5 promoted CRC proliferation and migration by regulating the ERK pathway, which may contribute to the clinical diagnosis and new treatment strategies for CRC.
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Zhirnov, O. P. "Asymmetric structure of the influenza A virus and novel function of the matrix protein M1." Problems of Virology, Russian journal 61, no. 4 (August 20, 2016): 149–54. http://dx.doi.org/10.18821/0507-4088-2016-61-4-149-154.
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Influenza virus is an enveloped virus. It comprises two major modules: external lipoprotein envelope and internal ribonucleoprotein (RNP) containing the genomic negative-strand RNA. Lipoprotein envelope contains four vital proteins: hemagglutinin (HA), neuraminidase (NA), transmembrane ionic channel M2, and minor amounts of nuclear export protein NEP. RNP contains RNA and four polypeptides: major nucleocapsid protein NP and three polymerase subunits PB1, PB2, PA. Both modules are linked with each other by matrix M1 maintaining the virus integrity. According to the structural function, NP and M1 are predominant in virus particle in the amounts of 1000 and 3000 molecules, respectively. In addition to the structural function, M1 plays a role in regulation of intracellular and nuclear migration of viral RNP and virus assembly, referred as budding process, at the plasma membrane in infected cells. The bipolar structure of the influenza virus characterized by asymmetric location of RNP and nonregular distribution of M1 and M2 inside the virion is reviewed. The role of M1 in maintaining the asymmetric structure of the virus particle and regulation of RNP transport inside virus particle is considered. First experimental data confirming (i) intravirion RNP transport and its outside exit directed by the M1 and (ii) the importance of this process in virus uncoating and initiation of infection in target cell are discussed. A novel class of antiviral agents activating ATP-ase of the early endosome compartment in the target cell is discussed.
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Yang, Weidong, and Siegfried M. Musser. "Nuclear import time and transport efficiency depend on importin β concentration." Journal of Cell Biology 174, no. 7 (September 18, 2006): 951–61. http://dx.doi.org/10.1083/jcb.200605053.
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Although many components and reaction steps necessary for bidirectional transport across the nuclear envelope (NE) have been characterized, the mechanism and control of cargo migration through nuclear pore complexes (NPCs) remain poorly understood. Single-molecule fluorescence microscopy was used to track the movement of cargos before, during, and after their interactions with NPCs. At low importin β concentrations, about half of the signal-dependent cargos that interacted with an NPC were translocated across the NE, indicating a nuclear import efficiency of ∼50%. At high importin β concentrations, the import efficiency increased to ∼80% and the transit speed increased approximately sevenfold. The transit speed and import efficiency of a signal-independent cargo was also increased by high importin β concentrations. These results demonstrate that maximum nucleocytoplasmic transport velocities can be modulated by at least ∼10-fold by the importin β concentration and therefore suggest a potential mechanism for regulating the speed of cargo traffic across the NE.
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Horn, Henning F., Dae In Kim, Graham D. Wright, Esther Sook Miin Wong, Colin L. Stewart, Brian Burke, and Kyle J. Roux. "A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton." Journal of Cell Biology 202, no. 7 (September 23, 2013): 1023–39. http://dx.doi.org/10.1083/jcb.201304004.
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Chromosome pairing is an essential meiotic event that ensures faithful haploidization and recombination of the genome. Pairing of homologous chromosomes is facilitated by telomere-led chromosome movements and formation of a meiotic bouquet, where telomeres cluster to one pole of the nucleus. In metazoans, telomere clustering is dynein and microtubule dependent and requires Sun1, an inner nuclear membrane protein. Here we provide a functional analysis of KASH5, a mammalian dynein-binding protein of the outer nuclear membrane that forms a meiotic complex with Sun1. This protein is related to zebrafish futile cycle (Fue), a nuclear envelope (NE) constituent required for pronuclear migration. Mice deficient in this Fue homologue are infertile. Males display meiotic arrest in which pairing of homologous chromosomes fails. These findings demonstrate that telomere attachment to the NE is insufficient to promote pairing and that telomere attachment sites must be coupled to cytoplasmic dynein and the microtubule system to ensure meiotic progression.
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Lingle, Wilma L., Ronald P. Clay, and David Porter. "Ultrastructural analysis of basidiosporogenesis in Panellus stypticus." Canadian Journal of Botany 70, no. 10 (October 1, 1992): 2017–27. http://dx.doi.org/10.1139/b92-251.
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The ultrastructure of events in basidiosporogenesis in Panellus stypticus was examined using conventional, aqueous-based fixation procedures and freeze substitution fixation following plunge freezing in liquid propane. Freeze substitution was superior in preserving cytological features and in retaining cell wall and extracellular materials. Synapsis, all stages of meiosis I (including prophase, metaphase, anaphase, and telophase), and prophase of meiosis II were observed. The nuclear envelope breaks down during meiosis I, temporarily reforms during interphase, and is at least partially broken down during meiosis II. Many stages of spore development, including sterigma initiation, sterigma elongation, organelle translocation, and nuclear migration, were observed. Spindle pole bodies with microtubule arrays were associated with nuclear migration into developing spores. Analysis of hymenial cells with gold-tagged lectins and enzymes revealed an α-amylase positive outer cell wall layer specific to basidiospores. Only after basidiospore release were surfaces of sterigmata and basidia similarly labeled. All cell walls observed were positive for wheat germ agglutinin, indicating the presence of chitin. Septa-delimiting basidiospores from sterigmata were heavily labeled with wheat germ agglutinin. This is the first investigation of basidiosporogenesis in a homobasidiomycete preserved for transmission electron microscopy by rapid freezing and freeze substitution. Key words: fungal cell walls, lectins, gold labeling, meiosis, rapid freezing, transmission electron microscopy.
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Robinson, John T., Edward J. Wojcik, Mark A. Sanders, Maura McGrail, and Thomas S. Hays. "Cytoplasmic Dynein Is Required for the Nuclear Attachment and Migration of Centrosomes during Mitosis in Drosophila." Journal of Cell Biology 146, no. 3 (August 9, 1999): 597–608. http://dx.doi.org/10.1083/jcb.146.3.597.
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Cytoplasmic dynein is a multisubunit minus-end–directed microtubule motor that serves multiple cellular functions. Genetic studies in Drosophila and mouse have demonstrated that dynein function is essential in metazoan organisms. However, whether the essential function of dynein reflects a mitotic requirement, and what specific mitotic tasks require dynein remains controversial. Drosophila is an excellent genetic system in which to analyze dynein function in mitosis, providing excellent cytology in embryonic and somatic cells. We have used previously characterized recessive lethal mutations in the dynein heavy chain gene, Dhc64C, to reveal the contributions of the dynein motor to mitotic centrosome behavior in the syncytial embryo. Embryos lacking wild-type cytoplasmic dynein heavy chain were analyzed by in vivo analysis of rhodamine-labeled microtubules, as well as by immu-nofluorescence in situ methods. Comparisons between wild-type and Dhc64C mutant embryos reveal that dynein function is required for the attachment and migration of centrosomes along the nuclear envelope during interphase/prophase, and to maintain the attachment of centrosomes to mitotic spindle poles. The disruption of these centrosome attachments in mutant embryos reveals a critical role for dynein function and centrosome positioning in the spatial organization of the syncytial cytoplasm of the developing embryo.
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Schaerer, Florian, Garry Morgan, Mark Winey, and Peter Philippsen. "Cnm67p Is a Spacer Protein of theSaccharomyces cerevisiaeSpindle Pole Body Outer Plaque." Molecular Biology of the Cell 12, no. 8 (August 2001): 2519–33. http://dx.doi.org/10.1091/mbc.12.8.2519.
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In Saccharomyces cerevisiae, the spindle pole body (SPB) is the functional homolog of the mammalian centrosome, responsible for the organization of the tubulin cytoskeleton. Cytoplasmic (astral) microtubules essential for the proper segregation of the nucleus into the daughter cell are attached at the outer plaque on the SPB cytoplasmic face. Previously, it has been shown that Cnm67p is an integral component of this structure; cells deleted forCNM67 are lacking the SPB outer plaque and thus experience severe nuclear migration defects. With the use of partial deletion mutants of CNM67, we show that the N- and C-terminal domains of the protein are important for nuclear migration. The C terminus, not the N terminus, is essential for Cnm67p localization to the SPB. On the other hand, only the N terminus is subject to protein phosphorylation of a yet unknown function. Electron microscopy of SPB serial thin sections reveals that deletion of the N- or C-terminal domains disturbs outer plaque formation, whereas mutations in the central coiled-coil domain of Cnm67p change the distance between the SPB core and the outer plaque. We conclude that Cnm67p is the protein that connects the outer plaque to the central plaque embedded in the nuclear envelope, adjusting the space between them by the length of its coiled-coil.
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Tanaka, Hisae, Yu Nishioka, Yuhki Yokoyama, Shigeki Higashiyama, Nariaki Matsuura, Shuji Matsuura, and Miki Hieda. "Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF-like domain independent manner." Biochemical and Biophysical Research Communications 420, no. 4 (April 2012): 721–26. http://dx.doi.org/10.1016/j.bbrc.2012.03.045.
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