scholarly journals Gaussian curvature dilutes the nuclear lamina, favoring nuclear rupture, especially at high strain rate

2021 ◽  
Author(s):  
Charlotte R Pfeifer ◽  
Michael P Tobin ◽  
Sangkyun Cho ◽  
Manasvita Vashisth ◽  
Lawrence J Dooling ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Gaussian Curvature ◽  
Cell Imaging ◽  
High Strain ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Strain Rates ◽  
Lamin B ◽  
Hypotonic Stress ◽  
Nuclear Rupture

Nuclear rupture has long been associated with deficits or defects in lamins, with recent results also indicating a role for actomyosin stress, but key physical determinants of rupture remain unclear. Here, lamin-B stably interacts with the nuclear membrane at sites of low Gaussian curvature yet dilutes at high-curvature to favor rupture, whereas lamin-A depletes similarly but only at high strain-rates. Live cell imaging of lamin-B1 gene-edited cancer cells is complemented by fixed-cell imaging of ruptured nuclei in: iPS-derived cells from progeria patients, cells within beating chick embryo hearts, and cancer cells that develop multiple ruptures in migrating through small pores. Dilution and curvature-dependent rupture fit a parsimonious model of a stiff filament that detaches from a curved surface, suggesting an elastic-type response of lamin-B, but rupture is also modestly suppressed by inhibiting myosin-II and by hypotonic stress, which slow the strain rates. Lamin-A dilution and nuclear rupture likelihood indeed increase above a threshold rate of pulling into small pipettes, suggesting a viscoplastic coupling to the envelope for protection against nuclear rupture.

scholarly journals Reduced Lamin A/C does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2383
Author(s):  
Francesco Roncato ◽  
Ofer Regev ◽  
Sara W. Feigelson ◽  
Sandeep Kumar Yadav ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Lung Metastasis ◽  
Metastatic Cancer ◽  
Nuclear Lamina ◽  
Transendothelial Migration ◽  
Soft Agar ◽  
Lamin A ◽  
And Migration

The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.

scholarly journals Lamin B constitutes an intermediate filament attachment site at the nuclear envelope.

1987 ◽  
Vol 105 (1) ◽  
pp. 117-125 ◽  
Author(s):  
S D Georgatos ◽  
G Blobel
Keyword(s):  
Plasma Membrane ◽  
Specific Binding ◽  
Attachment Site ◽  
Nuclear Lamina ◽  
Membrane Skeleton ◽  
Eukaryotic Cells ◽  
Lamin A ◽  
Lamin B ◽  
Nuclear Lamins

We found that urea extraction of turkey erythrocyte nuclear envelopes abolished their ability to bind exogenous 125I-vimentin, while, at the same time, it removed the nuclear lamins from the membranes. After purification of the lamins from such urea extracts, a specific binding between isolated vimentin and lamin B, or a lamin A + B hetero-oligomer, was detected by affinity chromatography. Similar analysis revealed that the 6.6-kD vimentin tail piece was involved in this interaction. By other approaches (quantitative immunoprecipitation, rate zonal sedimentation, turbidometric assays) a substoichiometric lamin B-vimentin binding was determined under in vitro conditions. It was also observed that anti-lamin B antibodies but not other sera (anti-lamin A, anti-ankyrin, preimmune) were able to block 70% of the binding of 125I-vimentin to native, vimentin-depleted, nuclear envelopes. These data, which were confirmed by using rat liver nuclear lamins, indicate that intermediate filaments may be anchored directly to the nuclear lamina, providing a continuous network connecting the plasma membrane skeleton with the karyoskeleton of eukaryotic cells.

scholarly journals Nuclear lamin A/C promotes cancer cell survival and lung metastasis without restricting transendothelial migration

2020 ◽  
Author(s):  
Francesco Roncato ◽  
Ofer Regev ◽  
Sara W. Feigelson ◽  
Sandeep Kumar Yadav ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lung Metastasis ◽  
Nuclear Lamina ◽  
Transendothelial Migration ◽  
Lamin A ◽  
Primary Tumors ◽  
Cancer Cell Survival

AbstractThe mechanisms by which the nuclear lamina of tumor cells controls their migration and survival are poorly understood. Lamin A and its variant lamin C are key nuclear lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C levels in two metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, elevated nuclear deformability and reduced heterochromatin. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown. Both cancer cells with lamin A/C knockdown grew normally in primary tumors and in vitro on rigid surfaces. Strikingly, however, both lamin A/C deficient melanoma and breast cancer cells grew poorly in 3D spheroids expanded in soft agar cultures. Experimental lung metastasis of both lamin A/C knockdown cells was also markedly reduced. Taken together, our results suggest that high content of lamin A/C in multiple cancer cells promotes cancer cell survival and ability to generate lung metastasis without compromising cancer cell emigration from lung vessels.

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.

Abstract MP230: Nuclear Rupture In A Mouse Model Of Lmna -related Cardiomyopathy Causes Cytoplasmic Exposure Of The Proinflammatory Signaling Protein Hmgb1

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kohta Ikegami ◽  
Alexis Stutzman ◽  
Sachie Ikegami ◽  
Omar Almakki ◽  
Sunny Liu ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Nuclear Dna ◽  
Nuclear Periphery ◽  
Direct Interaction ◽  
Nuclear Lamina ◽  
Underlying Disease ◽  
Sterile Inflammation ◽  
Lamin A ◽  
Reduced Ejection Fraction ◽  
Nuclear Rupture

Cardiomyopathies caused by mutations in LMNA, encoding nuclear Lamin A/C, are highly malignant and prevalent. How LMNA mutations cause cardiomyopathies remains unknown. We characterized cellular, molecular, and pathological evolution of mouse models of LMNA -related cardiomyopathy and provide evidence for a model in which nuclear rupture generates nuclear-localized proinflammatory signaling as a candidate molecular mechanism underlying disease pathogenesis. We observed that cardiomyocyte-specific, tamoxifen-inducible deletion of Lmna in adult mice ( Lmna CMKO ) caused a gradual reduction of Lamin A/C protein at the nuclear lamina, reflecting the slow turnover of Lamin A/C. A modest reduction of Lamin A/C in Lmna CMKO was sufficient to cause extensive fibrosis, reduced ejection fraction, and chamber dilation by 3 weeks after Lmna gene deletion. Lmna CMKO cardiomyocytes exhibited localized rupture of the nuclear envelope 2 weeks prior to the development of fibrosis and reduction of ejection fraction. Nuclear rupture in Lmna CMKO was immediately followed by an extensive upregulation of pro-inflammatory gene expression programs. We hypothesized that nuclear rupture might expose nuclear DNA to the cytoplasm thereby activating the pro-inflammatory cGas-STING cytosolic DNA sensing pathway. However, we did not observe localization of the cytosolic DNA sensor cGas to cytoplasmic DNA protruded from the ruptured nuclei in Lmna CMKO cardiomyocytes. Instead, we found that HMGB1, a potent proinflammatory protein normally sequestered in the nucleus, was released from the ruptured nuclei in Lmna CMKO cardiomyocytes. Mass spectrometry identified a strong interaction between Lamin A/C and HMGB1 in normal human fibroblast cells. Our data suggested that Lamin A/C tethers HMGB1 to the nuclear periphery by direct interaction and that reduction of Lamin A/C unleashes HMGB1 to the cytoplasm upon nuclear rupture. Future work will examine the hypothesis that cytoplasmic HMGB1 triggers pathogenic sterile inflammation leading to dilated cardiomyopathies in Lmna CMKO mice. In conclusion, we identified the nuclear rupture-induced cytoplasmic release of HMGB1 as a candidate mechanism underlying LMNA -related cardiomyopathies.

Cells of the cellular immune and hemopoietic system of the mouse lack lamins A/C: distinction versus other somatic cells

1990 ◽  
Vol 95 (4) ◽  
pp. 587-598
Author(s):  
R.A. Rober ◽  
H. Sauter ◽  
K. Weber ◽  
M. Osborn
Keyword(s):  
Adult Mouse ◽  
Somatic Cells ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Monocytic Cells ◽  
Lamin B ◽  
Nuclear Lamins ◽  
Almost All ◽  
Cellular Immune ◽  
Hemopoietic System

Almost all somatic cells in adult murine tissues express all three nuclear lamins (A, B, C). Here we demonstrate that cells of the hemopoietic system of the adult mouse are an exception in that they express only lamin B. Thus T and B lymphocytes as well as granulocytes and monocytic cells directly isolated from spleen, thymus, blood or bone marrow do not express lamin A/C but only lamin B. In agreement with this observation the murine hemopoietic cell lines EL4, BW5147, HK22, 70Z/3, SP2/0 and PAI express only lamin B. In immunoblotting experiments used to confirm the immunofluorescence data no lamin A/C expression was detected. However, we noticed that murine lamin B occurs in two isoforms, which can be distinguished immunologically. These results reinforce the idea that a functional nuclear lamina can be formed from lamin B alone. They also pose the question of whether cells lacking lamin A/C are more plastic in their developmental programs than those that express all three lamins.

scholarly journals Isoprenylation is required for the processing of the lamin A precursor.

1990 ◽  
Vol 110 (5) ◽  
pp. 1489-1499 ◽  
Author(s):  
L A Beck ◽  
T J Hosick ◽  
M Sinensky
Keyword(s):  
Gel Electrophoresis ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Two Dimensional ◽  
Cho Cell ◽  
Prelamin A ◽  
Lamin B ◽  
Isoprenoid Metabolism ◽  
Significant Difference ◽  
Metabolism Analysis

The nuclear lamina proteins, prelamin A, lamin B, and a 70-kD lamina-associated protein, are posttranslationally modified by a metabolite derived from mevalonate. This modification can be inhibited by treatment with (3-R,S)-3-fluoromevalonate, demonstrating that it is isoprenoid in nature. We have examined the association between isoprenoid metabolism and processing of the lamin A precursor in human and hamster cells. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by mevinolin (lovastatin) specifically depletes endogenous isoprenoid pools and inhibits the conversion of prelamin A to lamin A. Prelamin A processing is also blocked by mevalonate starvation of Mev-1, a CHO cell line auxotrophic for mevalonate. Moreover, inhibition of prelamin A processing by mevinolin treatment is rapidly reversed by the addition of exogenous mevalonate. Processing of prelamin A is, therefore, dependent on isoprenoid metabolism. Analysis of the conversion of prelamin A to lamin A by two independent methods, immunoprecipitation and two-dimensional nonequilibrium pH gel electrophoresis, demonstrates that a precursor-product relationship exists between prelamin A and lamin A. Analysis of R,S-[5-3H(N)]mevalonate-labeled cells shows that the rate of turnover of the isoprenoid group from prelamin A is comparable to the rate of conversion of prelamin A to lamin A. These results suggest that during the proteolytic maturation of prelamin A, the isoprenylated moiety is lost. A significant difference between prelamin A processing, and that of p21ras and the B-type lamins that undergo isoprenylation-dependent proteolytic maturation, is that the mature form of lamin A is no longer isoprenylated.

Solid Solution Effects and Deformation Micros trueture of Shock-Loaded Iron Manganese Alloys

1970 ◽  
Vol 28 ◽  
pp. 420-421
Author(s):  
A. Christou ◽  
J. V. Foltz ◽  
N. Brown
Keyword(s):  
Solid Solution ◽  
Shock Loading ◽  
High Strain ◽  
Local Stress ◽  
Strain Rates ◽  
Local Stress Concentration ◽  
Bcc Metals ◽  
Manganese Alloys ◽  
Iron Manganese ◽  
Transmission Microscope

In general, all BCC transition metals have been observed to twin under appropriate conditions. At the present time various experimental reports of solid solution effects on BCC metals have been made. Indications are that solid solution effects are important in the formation of twins. The formation of twins in metals and alloys may be explained in terms of dislocation mechanisms. It has been suggested that twins are nucleated by the achievement of local stress-concentration of the order of 15 to 45 times the applied stress. Prietner and Leslie have found that twins in BCC metals are nucleated at intersections of (110) and (112) or (112) and (112) type of planes.In this paper, observations are reported of a transmission microscope study of the iron manganese series under conditions in which twins both were and were not formed. High strain rates produced by shock loading provided the appropriate deformation conditions. The workhardening mechanisms of one alloy (Fe - 7.37 wt% Mn) were studied in detail.

Lamin B receptor: role on chromatin structure, cellular senescence and possibly aging

2020 ◽  
Vol 477 (14) ◽  
pp. 2715-2720
Author(s):  
Susana Castro-Obregón
Keyword(s):  
Cellular Senescence ◽  
Nuclear Membrane ◽  
Chromatin Structure ◽  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Chimeric Protein ◽  
Nuclear Lamina ◽  
Lamin B ◽  
Inner Nuclear Membrane ◽  
Lamin B Receptor

The nuclear envelope is composed by an outer nuclear membrane and an inner nuclear membrane, which is underlain by the nuclear lamina that provides the nucleus with mechanical strength for maintaining structure and regulates chromatin organization for modulating gene expression and silencing. A layer of heterochromatin is beneath the nuclear lamina, attached by inner nuclear membrane integral proteins such as Lamin B receptor (LBR). LBR is a chimeric protein, having also a sterol reductase activity with which it contributes to cholesterol synthesis. Lukasova et al. showed that when DNA is damaged by ɣ-radiation in cancer cells, LBR is lost causing chromatin structure changes and promoting cellular senescence. Cellular senescence is characterized by terminal cell cycle arrest and the expression and secretion of various growth factors, cytokines, metalloproteinases, etc., collectively known as senescence-associated secretory phenotype (SASP) that cause chronic inflammation and tumor progression when they persist in the tissue. Therefore, it is fundamental to understand the molecular basis for senescence establishment, maintenance and the regulation of SASP. The work of Lukasova et al. contributed to our understanding of cellular senescence establishment and provided the basis that lead to the further discovery that chromatin changes caused by LBR reduction induce an up-regulated expression of SASP factors. LBR dysfunction has relevance in several diseases and possibly in physiological aging. The potential bifunctional role of LBR on cellular senescence establishment, namely its role in chromatin structure together with its enzymatic activity contributing to cholesterol synthesis, provide a new target to develop potential anti-aging therapies.

Sign in / Sign up

Export Citation Format

Share Document