Lamins: building blocks or regulators of gene expression?

Hutchison, Christopher J.

doi:10.1038/nrm950

Cited by 265 publications

(217 citation statements)

References 110 publications

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“…However, they are also present within the nucleus [2]. In addition to participating in nuclear architecture, there is a growing body of evidence showing that lamin A/C plays a key role in gene transcription regulation, DNA repair and replication [1,3], and cell differentiation regulation [1,4,5]. The list of lamins A and C partners is regularly growing [2,[6][7][8][9], which confirms that these proteins are involved in multiple functions, some of which are still being unravelled.…”

Section: Introductionmentioning

confidence: 98%

Specific contribution of lamin A and lamin C in the development of laminopathies

Sylvius

Hathaway

Boudreau

et al. 2008

Experimental Cell Research

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Mutations in the lamin A/C gene are involved in multiple human disorders for which the pathophysiological mechanisms are partially understood. Conflicting results prevail regarding the organization of lamin A and C mutants within the nuclear envelope (NE) and on the interactions of each lamin to its counterpart. We over-expressed various lamin A and C mutants both independently and together in COS7 cells. When expressed alone, lamin A with cardiac/muscular disorder mutations forms abnormal aggregates inside the NE and not inside the nucleoplasm. Conversely, the equivalent lamin C organizes as intranucleoplasmic aggregates that never connect to the NE as opposed to wild type lamin C. Interestingly, the lamin C molecules present within these aggregates exhibit an abnormal increased mobility. When co-expressed, the complex formed by lamin A/C aggregates in the NE. Lamin A and C mutants for lipodystrophy behave similarly to the wild type. These findings reveal that lamins A and C may be differentially affected depending on the mutation. This results in multiple possible physiological consequences which likely contribute in the phenotypic variability of laminopathies. The inability of lamin C mutants to join the nuclear rim in the absence of lamin A is a potential pathophysiological mechanism for laminopathies.

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Section: Introductionmentioning

confidence: 98%

Specific contribution of lamin A and lamin C in the development of laminopathies

Sylvius

Hathaway

Boudreau

et al. 2008

Experimental Cell Research

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“…Finally, lamins have the ability to bind directly to DNA (Stierle et al, 2003) and to chromatin (Glass et al, 1993;Taniura et al, 1995) and indirectly via associations with proteins containing a LEM box (Lee et al, 2001;Martins et al, 2003). Thus, the list of possible functions of the A-type lamins includes maintenance of nuclear structural integrity, organisation of higher-order chromatin structure and control of gene expression (Hutchison, 2002). Nevertheless, it is an important finding that mutations in the lamin A gene can give rise to a range of diseases and in particular to premature aging.…”

Section: Introductionmentioning

confidence: 99%

Aging of Hutchinson–Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis

Bridger

Kill

2004

Experimental Gerontology

157

137

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Hutchinson -Gilford progeria syndrome is a rare genetic disorder that mimics certain aspects of aging prematurely. Recent work has revealed that mutations in the lamin A gene are a cause of the disease. We show here that cellular aging of Hutchinson -Gilford progeria syndrome fibroblasts is characterised by a period of hyperproliferation and terminates with a large increase in the rate of apoptosis. The occurrence of cells with abnormal nuclear morphology reported by others is shown to be a result of cell division since the fraction of these abnormalities increases with cellular age. Similarly, the proportion of cells with an abnormal or absent A-type lamina increases with age. These data provide clues as to the cellular basis for premature aging in HGPS and support the view that cellular senescence and tissue homeostasis are important factors in the normal aging process. q 2004 Elsevier Inc. All rights reserved.

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“…Mutations in LMNA, the gene encoding lamins A and C, were recently identified as the cause of HGPS (3,4). Lamins A and C are major constituents of the nuclear lamina, the meshwork of nuclear intermediate filaments that support the inner nuclear membrane and also extend throughout the nucleus (5). Other major components of the nuclear lamina are lamins B1 and B2, which are encoded by two distinct genes (6).…”

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confidence: 99%

Distinct structural and mechanical properties of the nuclear lamina in Hutchinson–Gilford progeria syndrome

Dahl

Scaffidi

Islam

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

341

370

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The nuclear lamina is a network of structural filaments, the A and B type lamins, located at the nuclear envelope and throughout the nucleus. Lamin filaments provide the nucleus with mechanical stability and support many basic activities, including gene regulation. Mutations in LMNA, the gene encoding A type lamins, cause numerous human diseases, including the segmental premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here we show that structural and mechanical properties of the lamina are altered in HGPS cells. We demonstrate by live-cell imaging and biochemical analysis that lamins A and C become trapped at the nuclear periphery in HGPS patient cells. Using micropipette aspiration, we show that the lamina in HGPS cells has a significantly reduced ability to rearrange under mechanical stress. Based on polarization microscopy results, we suggest that the lamins are disordered in the healthy nuclei, whereas the lamins in HGPS nuclei form orientationally ordered microdomains. The reduced deformability of the HGPS nuclear lamina possibly could be due to the inability of these orientationally ordered microdomains to dissipate mechanical stress. Surprisingly, intact HGPS cells exhibited a degree of resistance to acute mechanical stress similar to that of cells from healthy individuals. Thus, in contrast to the nuclear fragility seen in lmna null cells, the lamina network in HGPS cells has unique mechanical properties that might contribute to disease phenotypes by affecting responses to mechanical force and misregulation of mechanosensitive gene expression.laminopathy ͉ mechanics ͉ nucleus ͉ photobleaching ͉ micropipette aspiration H utchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that causes segmental premature aging in children. HGPS patients are mentally normal, but fail to reach full stature and experience hair loss, thin wrinkled skin, and joint stiffness, and usually die in their early teens of cardiovascular disease or stroke (1, 2). Mutations in LMNA, the gene encoding lamins A and C, were recently identified as the cause of HGPS (3, 4). Lamins A and C are major constituents of the nuclear lamina, the meshwork of nuclear intermediate filaments that support the inner nuclear membrane and also extend throughout the nucleus (5). Other major components of the nuclear lamina are lamins B1 and B2, which are encoded by two distinct genes (6). Most HGPS cases are caused by a de novo single-point mutation (G608G; GGCϾGGT) in one allele of LMNA (3, 4). This substitution activates a cryptic splice site in exon 11, which affects only the lamin A protein, and the mutant allele produces an alternatively spliced truncated variant of the lamin A mRNA lacking the 3Ј terminal 150 nt of exon 11. The resulting polypeptide, ⌬50 lamin A, has an internal deletion of 50 residues in the C-terminal tail domain and also lacks an endoproteolytic cleavage site required for normal processing of the lamin A precursor (3, 4, 7). HGPS patient fibroblasts often are characterized by numerous nuclear defe...

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Lamins: building blocks or regulators of gene expression?

Cited by 265 publications

References 110 publications

Specific contribution of lamin A and lamin C in the development of laminopathies

Specific contribution of lamin A and lamin C in the development of laminopathies

Aging of Hutchinson–Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis

Distinct structural and mechanical properties of the nuclear lamina in Hutchinson–Gilford progeria syndrome

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