scholarly journals Apico-basal cell compression regulates Lamin A/C levels in Epithelial tissues

2020 ◽  
Author(s):  
K Venkatesan Iyer ◽  
Natalie A. Dye ◽  
Suzanne Eaton ◽  
Frank Jülicher
Keyword(s):  
Basal Cell ◽  
Mdck Cells ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Mechanical Coupling ◽  
Nuclear Mechanics ◽  
Epithelial Tissues ◽  
Nuclear Lamin ◽  
Genetic Perturbations ◽  
Cell Shapes

ABSTRACTNuclear lamina bridges mechanical forces from the cytoskeleton to the nucleus, to initiate nuclear mechanotransduction. The concentration of nuclear Lamin proteins, particularly Lamin A/C is crucial for the mechanical properties of the nucleus and nuclear mechanotransduction. Recent studies in mesenchymal tissues show that the concentration of Lamin A/C scales with stiffness and concentration of the underlying extracellular matrix (ECM). But in epithelial tissues, that lack a strong cell-ECM interaction, it is still unclear how Lamin A/C is regulated. Here, we show that concentration of Lamin A/C in epithelial tissues scales with apico-basal compression of cells and is independent of ECM concentration. But, ectopically altering the concentration of Lamin A/C does not influence cell shapes in epithelial tissues. Using genetic perturbations in Drosophila epithelial tissues, we reveal that apico-basal cell compression regulates the concentration of Lamin A/C by deforming the nucleus. We observe a similar mechanism of Lamin A/C regulation in mammalian Madin Darby Canine Kidney (MDCK) cells suggesting that this mechanism is evolutionarily conserved. Taken together, our results reveal a unidirectional mechanical coupling between cell mechanics and nuclear mechanics via the regulation of Lamin A/C. We anticipate that mechanism of Lamin A/C regulation that we revealed, could form the basis for understanding nuclear mechanotransduction in epithelial tissues.

scholarly journals Apico-basal cell compression regulates Lamin A/C levels in epithelial tissues

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
K. Venkatesan Iyer ◽  
Anna Taubenberger ◽  
Salma Ahmed Zeidan ◽  
Natalie A. Dye ◽  
Suzanne Eaton ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Basal Cell ◽  
Strong Interaction ◽  
Nuclear Protein ◽  
Lamin A ◽  
Nuclear Deformation ◽  
Tissue Stiffness ◽  
Epithelial Tissues ◽  
Genetic Perturbations

AbstractThe levels of nuclear protein Lamin A/C are crucial for nuclear mechanotransduction. Lamin A/C levels are known to scale with tissue stiffness and extracellular matrix levels in mesenchymal tissues. But in epithelial tissues, where cells lack a strong interaction with the extracellular matrix, it is unclear how Lamin A/C is regulated. Here, we show in epithelial tissues that Lamin A/C levels scale with apico-basal cell compression, independent of tissue stiffness. Using genetic perturbations in Drosophila epithelial tissues, we show that apico-basal cell compression regulates the levels of Lamin A/C by deforming the nucleus. Further, in mammalian epithelial cells, we show that nuclear deformation regulates Lamin A/C levels by modulating the levels of phosphorylation of Lamin A/C at Serine 22, a target for Lamin A/C degradation. Taken together, our results reveal a mechanism of Lamin A/C regulation which could provide key insights for understanding nuclear mechanotransduction in epithelial tissues.

scholarly journals Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model.

2019 ◽  
Vol 5 (3) ◽  
pp. eaav5078 ◽  
Author(s):  
Ying Ao ◽  
Jie Zhang ◽  
Zuojun Liu ◽  
Minxian Qian ◽  
Yao Li ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Lamin A ◽  
Catalytic Core ◽  
Prelamin A ◽  
Damage Repair ◽  
Nuclear Lamin ◽  
Activity Loss ◽  
Ck2 Kinase

Defective nuclear lamina protein lamin A is associated with premature aging. Casein kinase 2 (CK2) binds the nuclear lamina, and inhibiting CK2 activity induces cellular senescence in cancer cells. Thus, it is feasible that lamin A and CK2 may cooperate in the aging process. Nuclear CK2 localization relies on lamin A and the lamin A carboxyl terminus physically interacts with the CK2α catalytic core and inhibits its kinase activity. Loss of lamin A inLmna-knockout mouse embryonic fibroblasts (MEFs) confers increased CK2 activity. Conversely, prelamin A that accumulates inZmpste24-deficent MEFs exhibits a high CK2α binding affinity and concomitantly reduces CK2 kinase activity. Permidine treatment activates CK2 by releasing the interaction between lamin A and CK2, promoting DNA damage repair and ameliorating progeroid features. These data reveal a previously unidentified function for nuclear lamin A and highlight an essential role for CK2 in regulating senescence and aging.

scholarly journals SUN1 Interacts with Nuclear Lamin A and Cytoplasmic Nesprins To Provide a Physical Connection between the Nuclear Lamina and the Cytoskeleton

2006 ◽  
Vol 26 (10) ◽  
pp. 3738-3751 ◽  
Author(s):  
Farhana Haque ◽  
David J. Lloyd ◽  
Dawn T. Smallwood ◽  
Carolyn L. Dent ◽  
Catherine M. Shanahan ◽  
...  
Keyword(s):  
Binding Protein ◽  
Nuclear Lamina ◽  
Integral Membrane Protein ◽  
Actin Binding ◽  
Lamin A ◽  
Terminal Domain ◽  
Cytoskeletal Network ◽  
Nuclear Lamin ◽  
Nuclear Component ◽  
Two Hybrid

ABSTRACT Nuclear migration and positioning within cells are critical for many developmental processes and are governed by the cytoskeletal network. Although mechanisms of nuclear-cytoskeletal attachment are unclear, growing evidence links a novel family of nuclear envelope (NE) proteins that share a conserved C-terminal SUN (Sad1/UNC-84 homology) domain. Analysis of Caenorhabditis elegans mutants has implicated UNC-84 in actin-mediated nuclear positioning by regulating NE anchoring of a giant actin-binding protein, ANC-1. Here, we report the identification of SUN1 as a lamin A-binding protein in a yeast two-hybrid screen. We demonstrate that SUN1 is an integral membrane protein located at the inner nuclear membrane. While the N-terminal domain of SUN1 is responsible for detergent-resistant association with the nuclear lamina and lamin A binding, lamin A/C expression is not required for SUN1 NE localization. Furthermore, SUN1 does not interact with type B lamins, suggesting that NE localization is ensured by binding to an additional nuclear component(s), most likely chromatin. Importantly, we find that the luminal C-terminal domain of SUN1 interacts with the mammalian ANC-1 homologs nesprins 1 and 2 via their conserved KASH domain. Our data provide evidence of a physical nuclear-cytoskeletal connection that is likely to be a key mechanism in nuclear-cytoplasmic communication and regulation of nuclear position.

scholarly journals Endothelial nuclear lamina is not required for glucocorticoid receptor nuclear import but does affect receptor-mediated transcription activation

2013 ◽  
Vol 305 (3) ◽  
pp. C309-C322 ◽  
Author(s):  
Arman Nayebosadri ◽  
Julie Y. Ji
Keyword(s):  
Shear Stress ◽  
Glucocorticoid Receptor ◽  
Transcriptional Activation ◽  
Protein Function ◽  
Transcriptional Activity ◽  
Nuclear Translocation ◽  
Nuclear Lamina ◽  
Luciferase Reporter ◽  
Lamin A ◽  
Nuclear Mechanics

The lamina serves to maintain the nuclear structure and stiffness while acting as a scaffold for heterochromatin and many transcriptional proteins. Its role in endothelial mechanotransduction, specifically how nuclear mechanics impact gene regulation under shear stress, is not fully understood. In this study, we successfully silenced lamin A/C in bovine aortic endothelial cells to determine its role in both glucocorticoid receptor (GR) nuclear translocation and glucocorticoid response element (GRE) transcriptional activation in response to dexamethasone and shear stress. Nuclear translocation of GR, an anti-inflammatory nuclear receptor, in response to dexamethasone or shear stress (5, 10, and 25 dyn/cm2) was observed via time-lapse cell imaging and quantified using a Bayesian image analysis algorithm. Transcriptional activity of the GRE promoter was assessed using a dual-luciferase reporter plasmid. We found no dependence on nuclear lamina for GR translocation from the cytoplasm into the nucleus. However, the absence of lamin A/C led to significantly increased expression of luciferase under dexamethasone and shear stress induction as well as changes in histone protein function. PCR results for NF-κB inhibitor alpha (NF-κBIA) and dual specificity phosphatase 1 (DUSP1) genes further supported our luciferase data with increased expression in the absence of lamin. Our results suggest that absence of lamin A/C does not hinder passage of GR into the nucleus, but nuclear lamina is important to properly regulate GRE transcription. Nuclear lamina, rather than histone deacetylase (HDAC), is a more significant mediator of shear stress-induced transcriptional activity, while dexamethasone-initiated transcription is more HDAC dependent. Our findings provide more insights into the molecular pathways involved in nuclear mechanotransduction.

scholarly journals Pathway of incorporation of microinjected lamin A into the nuclear envelope.

1992 ◽  
Vol 119 (4) ◽  
pp. 725-735 ◽  
Author(s):  
A E Goldman ◽  
R D Moir ◽  
M Montag-Lowy ◽  
M Stewart ◽  
R D Goldman
Keyword(s):  
Time Course ◽  
Nuclear Lamina ◽  
Lamin A ◽  
3T3 Cells ◽  
Intermediate Filament Proteins ◽  
Daughter Cells ◽  
Nuclear Lamin ◽  
Rapid Accumulation ◽  
Nuclear Structures ◽  
Cycle Dependent

When microinjected into the cytoplasm of 3T3 cells, biotinylated human lamin A rapidly enters the nucleus and gradually becomes incorporated into the nuclear lamina region as determined by immunofluorescence. The incorporation of the microinjected material takes several hours and progresses through a series of morphologically identifiable stages. Within minutes after microinjection, lamin A is found in spots distributed throughout the nucleus, except in nucleolar regions. Over a time course of up to 6 h, these spots appear to decrease in size and number as the biotinylated lamin A becomes associated with the endogenous nuclear lamina. Eventually, the typical nuclear rim staining pattern normally revealed by immunofluorescence with nuclear lamin antibodies is seen with antibiotin. This latter rim staining property is passed on to daughter cells following mitosis. These results indicate that the microinjected biotinylated nuclear lamin A retains those properties required for its integration into the lamina, as well as those necessary for the disassembly and subsequent reassembly of the nuclear lamina during cell division. The initial rapid accumulation into foci and the subsequent slower incorporation into the nuclear lamina appear to be analogous to the stages of incorporation following the microinjection of cytoskeletal intermediate filament proteins such as vimentin and keratin (Vikstrom, K., G. G. Borisy, and R. D. Goldman. 1989. Proc. Natl. Acad. Sci. USA. 86:549-553; Miller, R. K., K. Vikstrom, and R. D. Goldman. 1991. J. Cell Biol. 113:843-855). Foci are also observed in some uninjected cells using nuclear lamin antibodies, indicating that these features are a genuine component of nuclear substructure. Evidence is presented that shows the appearance of these nuclear structures is cell cycle dependent.

scholarly journals The nucleoporin Nup88 is interacting with nuclear lamin A

2011 ◽  
Vol 22 (7) ◽  
pp. 1080-1090 ◽  
Author(s):  
Yvonne C. Lussi ◽  
Ilona Hügi ◽  
Eva Laurell ◽  
Ulrike Kutay ◽  
Birthe Fahrenkrog
Keyword(s):  
Nuclear Lamina ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Lamin A ◽  
Xenopus Laevis Oocyte ◽  
Tail Domain ◽  
Intermediate Filament Proteins ◽  
Nuclear Lamin ◽  
In Cells

Nuclear pore complexes (NPCs) are embedded in the nuclear envelope (NE) and mediate bidirectional nucleocytoplasmic transport. Their spatial distribution in the NE is organized by the nuclear lamina, a meshwork of nuclear intermediate filament proteins. Major constituents of the nuclear lamina are A- and B-type lamins. In this work we show that the nuclear pore protein Nup88 binds lamin A in vitro and in vivo. The interaction is mediated by the N-terminus of Nup88, and Nup88 specifically binds the tail domain of lamin A but not of lamins B1 and B2. Expression of green fluorescent protein–tagged lamin A in cells causes a masking of binding sites for Nup88 antibodies in immunofluorescence assays, supporting the interaction of lamin A with Nup88 in a cellular context. The epitope masking disappears in cells expressing mutants of lamin A that are associated with laminopathic diseases. Consistently, an interaction of Nup88 with these mutants is disrupted in vitro. Immunoelectron microscopy using Xenopus laevis oocyte nuclei further revealed that Nup88 localizes to the cytoplasmic and nuclear face of the NPC. Together our data suggest that a pool of Nup88 on the nuclear side of the NPC provides a novel, unexpected binding site for nuclear lamin A.

scholarly journals Nuclear Lamin A/C Expression Is a Key Determinant of Paclitaxel Sensitivity

2021 ◽  
Author(s):  
Elizabeth R. Smith ◽  
Justin Leal ◽  
Celina Amaya ◽  
Bing Li ◽  
Xiang-Xi Xu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Nuclear Lamina ◽  
Current Treatment ◽  
Nuclear Shape ◽  
Ovarian Cancer Cells ◽  
Lamin A ◽  
Cancer Therapies ◽  
Normal Cells ◽  
Nuclear Lamin

Paclitaxel is a key member of the Taxane (Taxol/paclitaxel, docetaxel/taxotere) family of successful drugs used in the current treatment of several solid tumors, including ovarian cancer. The molecular target of Taxol/paclitaxel has been identified as tubulin, and paclitaxel binding alters the dynamics and thus stabilizes microtubule bundles. Traditionally, the anti-cancer mechanism of paclitaxel has been thought to originate from its interfering with the role of microtubules in mitosis, resulting in mitotic arrest and subsequent apoptosis. However, recent evidence suggests that paclitaxel operates in cancer therapies via an as-yet-undefined mechanism rather than as a mitotic inhibitor. We found that paclitaxel caused a striking break up of nuclei (referred to as multimicronucleation) in malignant ovarian cancer cells but not in normal cells, and susceptibility to undergo nuclear fragmentation and cell death correlated with a reduction in nuclear lamina proteins, Lamin A/C. Lamin A/C proteins are commonly lost, reduced, or heterogeneously expressed in ovarian cancer, accounting for the aberration of nuclear shape in malignant cells. Mouse ovarian epithelial cells isolated from Lamin A/C null mice were highly sensitive to paclitaxel and underwent nuclear breakage, compared to control wildtype cells. Forced over-expression of Lamin A/C led to resistance to paclitaxel-induced nuclear breakage in cancer cells. Additionally, paclitaxel-induced multimicronucleation occurred independently of cell division that was achieved either by the withdrawal of serum or addition of mitotic inhibitors. These results provide a new understanding for the mitotic-independent mechanism for paclitaxel killing of cancer cells, where paclitaxel induces nuclear breakage in malignant cancer cells that have a malleable nucleus, but not in normal cells that have a stiffer nuclear envelope. As such, we identify that reduced nuclear Lamin A/C protein levels correlate with nuclear shape deformation and is a key determinant of paclitaxel sensitivity of cancer cells.

scholarly journals Differential expression of nuclear lamin proteins during chicken development.

1987 ◽  
Vol 105 (1) ◽  
pp. 577-587 ◽  
Author(s):  
C F Lehner ◽  
R Stick ◽  
H M Eppenberger ◽  
E A Nigg
Keyword(s):  
Embryonic Development ◽  
Germ Line ◽  
Nuclear Architecture ◽  
Nuclear Lamina ◽  
Cell Types ◽  
Lamin A ◽  
Two Dimensional Gel Electrophoresis ◽  
Tissue Specific ◽  
Nuclear Lamin ◽  
Quantitative Immunoblotting

By immunocytochemistry, quantitative immunoblotting, and two-dimensional gel electrophoresis, we have analyzed the distribution of nuclear lamin proteins during chicken embryonic development. Whereas no qualitative differences in the patterns of expression of lamins A, B1, and B2 were observed during gametogenesis in either the female or the male germ line, profound changes in the composition of the nuclear lamina occurred during the development of somatic tissues. Most unexpectedly, early chicken embryos were found to contain little if any lamin A, although they contained substantial amounts of lamins B1 and B2. During embryonic development, lamin A became increasingly prominent, whereas the amounts of lamin B1 decreased in many tissues. Interestingly, the extent and the developmental timing of these changes displayed pronounced tissue-specific variations. Lamin B2 was expressed in fairly constant amounts in all cell types investigated (except for pachytene-stage germ cells). These results have implications for the purported functional specializations of individual lamin proteins. In addition, they suggest that alterations in the composition of the nuclear lamina may be important for the establishment of cell- or tissue-specific differences in nuclear architecture.

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