Impaired nuclear functions lead to increased senescence and inefficient differentiation in human myoblasts with a dominant p.R545C mutation in the LMNA gene

Kandert, Sebastian; Wehnert, Manfred; Müller, C. R.; Buendia, Brigitte; Dabauvalle, Marie-Christine

doi:10.1016/j.ejcb.2009.06.002

Cited by 32 publications

(17 citation statements)

References 72 publications

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“…As further evidence for this role, LB1 levels decrease dramatically as cells become senescent, and when LB1 is depleted from cells, they become prematurely senescent. Although LA, LC, and LB2 do not appreciably decrease in their expression during senescence, mutations in LMNA and alterations in the amount of wildtype LA and the unprocessed precursor of LA (pre-LA) have been shown to cause premature senescence (Huang et al 2008;Kandert et al 2009;Taimen et al 2009;Ragnauth et al 2010;Moiseeva et al 2011). One of these LMNA mutations, which is the most prevalent mutation causing Hutchinson-Gilford progeria syndrome (HGPS), results in the accumulation of a permanently farnesylated form of LA with a 50-amino-acid deletion near the C terminus, called LAD50/progerin.…”

Section: Discussionmentioning

confidence: 99%

The role of nuclear lamin B1 in cell proliferation and senescence

Shimi¹,

Butin‐Israeli²,

Adam³

et al. 2011

Genes Dev.

467

430

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Nuclear lamin B1 (LB1) is a major structural component of the nucleus that appears to be involved in the regulation of many nuclear functions. The results of this study demonstrate that LB1 expression in WI-38 cells decreases during cellular senescence. Premature senescence induced by oncogenic Ras also decreases LB1 expression through a retinoblastoma protein (pRb)-dependent mechanism. Silencing the expression of LB1 slows cell proliferation and induces premature senescence in WI-38 cells. The effects of LB1 silencing on proliferation require the activation of p53, but not pRb. However, the induction of premature senescence requires both p53 and pRb. The proliferation defects induced by silencing LB1 are accompanied by a p53-dependent reduction in mitochondrial reactive oxygen species (ROS), which can be rescued by growth under hypoxic conditions. In contrast to the effects of LB1 silencing, overexpression of LB1 increases the proliferation rate and delays the onset of senescence of WI-38 cells. This overexpression eventually leads to cell cycle arrest at the G1/S boundary. These results demonstrate the importance of LB1 in regulating the proliferation and senescence of human diploid cells through a ROS signaling pathway.

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Section: Discussionmentioning

confidence: 99%

The role of nuclear lamin B1 in cell proliferation and senescence

Shimi¹,

Butin‐Israeli²,

Adam³

et al. 2011

Genes Dev.

467

430

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“…Consistent with this, alterations in the distribution of heterochromatin marks, such as histone H3 lysine 9 methylation (H3K9me) and H3K27me, have been observed in murine and human myoblast cells harboring mutations in the LMNA gene [20,21]. Mutations in NE proteins can also lead to a reduction of transcription of muscle differentiation genes [22].…”

Section: Introductionmentioning

confidence: 86%

Genome-wide analysis links emerin to neuromuscular junction activity in Caenorhabditis elegans

et al. 2014

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BackgroundLaminopathies are diseases characterized by defects in nuclear envelope structure. A well-known example is Emery-Dreifuss muscular dystrophy, which is caused by mutations in the human lamin A/C and emerin genes. While most nuclear envelope proteins are ubiquitously expressed, laminopathies often affect only a subset of tissues. The molecular mechanisms underlying these tissue-specific manifestations remain elusive. We hypothesize that different functional subclasses of genes might be differentially affected by defects in specific nuclear envelope components.ResultsHere we determine genome-wide DNA association profiles of two nuclear envelope components, lamin/LMN-1 and emerin/EMR-1 in adult Caenorhabditis elegans. Although both proteins bind to transcriptionally inactive regions of the genome, EMR-1 is enriched at genes involved in muscle and neuronal function. Deletion of either EMR-1 or LEM-2, another integral envelope protein, causes local changes in nuclear architecture as evidenced by altered association between DNA and LMN-1. Transcriptome analyses reveal that EMR-1 and LEM-2 are associated with gene repression, particularly of genes implicated in muscle and nervous system function. We demonstrate that emr-1, but not lem-2, mutants are sensitive to the cholinesterase inhibitor aldicarb, indicating altered activity at neuromuscular junctions.ConclusionsWe identify a class of elements that bind EMR-1 but do not associate with LMN-1, and these are enriched for muscle and neuronal genes. Our data support a redundant function of EMR-1 and LEM-2 in chromatin anchoring to the nuclear envelope and gene repression. We demonstrate a specific role of EMR-1 in neuromuscular junction activity that may contribute to Emery-Dreifuss muscular dystrophy in humans.

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“…As further evidence for the importance of the lamin A/pRb interaction, the expression of either an AD-EDMD lamin A mutant protein or the HGPS lamin A mutant protein, progerin, results in the inhibition of the phosphorylation of pRb (Markiewicz et al 2005;Dechat et al 2007). In the case of the AD-EDMD mutation, a further decrease in pRb levels along with the failure to hyperphosphorylate the available pRB inhibits myoblast differentiation (Favreau et al 2004;Kandert et al 2009). In adipocyte differentiation, the overexpression of either wild-type lamin A or a lamin A mutant associated with familial partial lipodystrophy impairs the potential of mouse fibroblasts to differentiate into mature adipocytes; and LMNA 2/2 mouse embryonic fibroblasts differentiate more readily into fat-containing cells compared to control cells (Boguslavsky et al 2006).…”

Section: Nuclear Laminsmentioning

confidence: 99%

Nuclear Lamins

Dechat¹,

Adam²,

Taimen³

et al. 2010

Cold Spring Harbor Perspectives in Biology

364

388

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The nuclear lamins are type V intermediate filament proteins that are critically important for the structural properties of the nucleus. In addition, they are involved in the regulation of numerous nuclear processes, including DNA replication, transcription and chromatin organization. The developmentally regulated expression of lamins suggests that they are involved in cellular differentiation. Their assembly dynamic properties throughout the cell cycle, particularly in mitosis, are influenced by posttranslational modifications. Lamins may regulate nuclear functions by direct interactions with chromatin and determining the spatial organization of chromosomes within the nuclear space. They may also regulate chromatin functions by interacting with factors that epigenetically modify the chromatin or directly regulate replication or transcription.

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Impaired nuclear functions lead to increased senescence and inefficient differentiation in human myoblasts with a dominant p.R545C mutation in the LMNA gene

Cited by 32 publications

References 72 publications

The role of nuclear lamin B1 in cell proliferation and senescence

The role of nuclear lamin B1 in cell proliferation and senescence

Genome-wide analysis links emerin to neuromuscular junction activity in Caenorhabditis elegans

Nuclear Lamins

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