Amphibian oocyte nuclei expressing lamin A with the progeria mutation E145K exhibit an increased elastic modulus

Kaufmann, Anna; Heinemann, Fabian; Radmacher, Manfred; Stick, Reimer

doi:10.4161/nucl.2.4.16119

Cited by 33 publications

(35 citation statements)

References 54 publications

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“…Consistent with our results, the nuclear properties of Progerin-transfected Xenopus nuclei showed an increased Young’s modulus that rendered the cells less elastic [87]. Furthermore, melanoma cells transfected with Progerin had a stiffened nucleoskeleton and impaired invasion as compared with the mock control cells [88].…”

Section: Discussionsupporting

confidence: 80%

Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of neuroblastoma cells

et al. 2017

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Nuclear lamins support the nuclear envelope and provide anchorage sites for chromatin. They are involved in DNA synthesis, transcription, and replication. It has previously been reported that the lack of Lamin A/C expression in lymphoma and leukaemia is due to CpG island promoter hypermethylation. Here, we provide evidence that Lamin A/C is silenced via this mechanism in a subset of neuroblastoma cells. Moreover, Lamin A/C expression can be restored with a demethylating agent. Importantly, Lamin A/C reintroduction reduced cell growth kinetics and impaired migration, invasion, and anchorage-independent cell growth. Cytoskeletal restructuring was also induced. In addition, the introduction of lamin Δ50, known as Progerin, caused senescence in these neuroblastoma cells. These cells were stiffer and developed a cytoskeletal structure that differed from that observed upon Lamin A/C introduction. Of relevance, short hairpin RNA Lamin A/C depletion in unmethylated neuroblastoma cells enhanced the aforementioned tumour properties. A cytoskeletal structure similar to that observed in methylated cells was induced. Furthermore, atomic force microscopy revealed that Lamin A/C knockdown decreased cellular stiffness in the lamellar region. Finally, the bioinformatic analysis of a set of methylation arrays of neuroblastoma primary tumours showed that a group of patients (around 3%) gives a methylation signal in some of the CpG sites located within the Lamin A/C promoter region analysed by bisulphite sequencing PCR. These findings highlight the importance of Lamin A/C epigenetic inactivation for a subset of neuroblastomas, leading to enhanced tumour properties and cytoskeletal changes. Additionally, these findings may have treatment implications because tumour cells lacking Lamin A/C exhibit more aggressive behaviour.

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Section: Discussionsupporting

confidence: 80%

Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of neuroblastoma cells

et al. 2017

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“…Advances in cryo-electron tomography may eventually enable more accurate visualization of the nuclear lamina in somatic cells [17]. Ectopic expression of human lamins in Xenopus oocytes indicates that A-type lamins form a thick (up to 100 nm) network and that B-type lamins form a thin fibrous meshwork closely associated with the inner nuclear membrane, likely due to their farnesyl lipid anchor [18,19]. (See Box 1 for a comparison of common animal models used to study lamins.)…”

Section: Structural Organization Of Nuclear Laminsmentioning

confidence: 99%

“…Contrary to the effect of EDMD- and DCM-causing mutations, lamin A mutations responsible for Hutchinson-Gilford progeria syndrome (HGPS) cause increased stiffness in HGPS patient cells [50,51] and when expressed in Xenopus oocytes [19]. Interestingly, fibroblasts from HGPS patients nonetheless have an increased susceptibility to mechanically induced cell death [50].…”

Section: Broken Nuclei Lead To Broken Hearts (And Muscle) – the Effecmentioning

confidence: 99%

Broken nuclei – lamins, nuclear mechanics, and disease

Davidson

Lammerding

2014

Trends in Cell Biology

249

250

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Mutations in lamins, which are ubiquitous nuclear intermediate filaments, lead to a variety of disorders, including muscular dystrophy and dilated cardiomyopathy. Lamins provide nuclear stability, help connect the nucleus to the cytoskeleton, and can modulate chromatin organization and gene expression. Nonetheless, the diverse functions of lamins remain incompletely understood. Here, we focus on the role of lamins on nuclear mechanics and its implication in human diseases. Recent findings suggest that lamin mutations can decrease nuclear stability, increase nuclear fragility, and disturb mechanotransduction signaling, possibly explaining the muscle-specific defects in many laminopathies. At the same time, altered lamin expression has been reported in many cancers, where the resulting increased nuclear deformability could enhance the ability of cells to transit tight interstitial spaces, promoting metastasis.

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“…These approaches include micropipette aspiration [89–93], atomic force microscopy [91,94–96], cell stretching [14,97–99], tracking of particles within the nucleoplasm [100], and, most recently, optical stretching [101] and measuring transit times through microfluidic constriction channels [102,103]. These experiments have revealed that the nucleus exhibits both elastic (the nuclear lamina) and viscoelastic (the nuclear interior) behavior and is typically ~2–10 times stiffer than the surrounding cytoplasm [99,104,93,105].…”

Section: Nuclear Mechanics and Mechanotransductionmentioning

confidence: 99%

Nuclear Mechanics in Cancer

Denais

Lammerding

2014

Advances in Experimental Medicine and Biology

139

122

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Despite decades of research, cancer metastasis remains an incompletely understood process that is as complex as it is devastating. In recent years, there has been an increasing push to investigate the biomechanical aspects of tumorigenesis, complementing the research on genetic and biochemical changes. In contrast to the high genetic variability encountered in cancer cells, almost all metastatic cells are subject to the same physical constraints as they leave the primary tumor, invade surrounding tissues, transit through the circulatory system, and finally infiltrate new tissues. Advances in live cell imaging and other biophysical techniques, including measurements of subcellular mechanics, have yielded stunning new insights into the physics of cancer cells. While much of this research has been focused on the mechanics of the cytoskeleton and the cellular microenvironment, it is now emerging that the mechanical properties of the cell nucleus and its connection to the cytoskeleton may play a major role in cancer metastasis, as deformation of the large and stiff nucleus presents a substantial obstacle during the passage through the dense interstitial space and narrow capillaries. Here, we present an overview of the molecular components that govern the mechanical properties of the nucleus and we discuss how changes in nuclear structure and composition observed in many cancers can modulate nuclear mechanics and promote metastatic processes. Improved insights into this interplay between nuclear mechanics and metastatic progression may have powerful implications in cancer diagnostics and therapy and may reveal novel therapeutic targets for pharmacological inhibition of cancer cell invasion.

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Amphibian oocyte nuclei expressing lamin A with the progeria mutation E145K exhibit an increased elastic modulus

Cited by 33 publications

References 54 publications

Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of neuroblastoma cells

Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of neuroblastoma cells

Broken nuclei – lamins, nuclear mechanics, and disease

Nuclear Mechanics in Cancer

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