Proteins that bind A-type lamins: integrating isolated clues

Zastrow, Michael S.; Vlcek, Sylvia; Wilson, Katherine L.

doi:10.1242/jcs.01102

Cited by 202 publications

(195 citation statements)

References 91 publications

(105 reference statements)

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“…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. For instance, it has recently been shown that lamins A and C are tightly connected to the cytoskeleton, thus revealing a nuclear-cytoskeletal continuity [10].…”

Section: Introductionmentioning

confidence: 97%

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: 97%

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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“…Entry into and maintenance of cell cycle arrest is essential for cellular differentiation. In addition, pRB is important for muscle and fat cell differentiation (34), as well as cellular senescence (50), suggesting that deregulated pRB activity could play a role in the pathology associated with laminopathies (14,36,57,61,75,78,79).Overexpression of p16 ink4a inhibits cyclin D-dependent kinase activity leading to hypophosphorylated pRB, reduced E2F activity, and arrest in the G 1 phase of the cell cycle (60). Cells lacking pRB are refractory to arrest by p16 ink4a (8,33,38,43).…”

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confidence: 99%

“…Also unresolved is why missense mutations in the same gene can lead to so many sometimes nonoverlapping diseases. We and others have considered the possibility that deregulated pRB function might underlie some of the pathologies associated with LMNA mutation (26,79). By this reasoning, reintroduction of lamin A disease mutants into Lmna Ϫ/Ϫ cells might not restore pRB protein levels and p16 ink4a responsiveness.…”

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confidence: 99%

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Stabilization of the Retinoblastoma Protein by A-Type Nuclear Lamins Is Required for INK4A-Mediated Cell Cycle Arrest

Nitta¹,

Jameson²,

Kudlow

et al. 2006

Molecular and Cellular Biology

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Mutations in the LMNA gene, which encodes all A-type lamins, including lamin A and lamin C, cause a variety of tissue-specific degenerative diseases termed laminopathies. Little is known about the pathogenesis of these disorders. Previous studies have indicated that A-type lamins interact with the retinoblastoma protein (pRB). Here we probe the functional consequences of this association and further examine links between nuclear structure and cell cycle control. Since pRB is required for cell cycle arrest by p16 ink4a , we tested the responsiveness of multiple lamin A/C-depleted cell lines to overexpression of this CDK inhibitor and tumor suppressor. We find that the loss of A-type lamin expression results in marked destabilization of pRB. This reduction in pRB renders cells resistant to p16 ink4a -mediated G 1 arrest. Reintroduction of lamin A, lamin C, or pRB restores p16 ink4a -responsiveness to Lmna ؊/؊ cells. An array of lamin A mutants, representing a variety of pathologies as well as lamin A processing mutants, was introduced into Lmna ؊/؊ cells. Of these, a mutant associated with mandibuloacral dysplasia (MAD R527H), as well as two lamin A processing mutants, but not other disease-associated mutants, failed to restore p16 ink4a responsiveness. Although our findings do not rule out links between altered pRB function and laminopathies, they fail to support such an assertion. These findings do link lamin A/C to the functional activation of a critical tumor suppressor pathway and further the possibility that somatic mutations in LMNA contribute to tumor progression.A-type lamins are intermediate filament proteins that have been linked to the organization and maintenance of nuclear structure. In most differentiated tissues, A-type lamins (predominantly lamins A and C), along with lamin B, comprise the meshwork underlying the inner nuclear membrane known as the nuclear lamina (63). Unlike lamin C, lamin A contains a carboxy-terminal CaaX motif and must undergo a series of posttranslational modifications to form the mature lamin A (77). In particular, the cysteine of the CaaX motif in lamin A is isoprenylated, followed by cleavage of the aaX and carboxymethylation of the C-terminal cysteine (72). Lastly, a second cleavage event by Zmpste24 removes the last 15 amino acids to yield the mature lamin A (3, 13, 74).Mutations within the LMNA gene cause a variety of human disorders collectively known as laminopathies. These include progeria syndromes and dystrophies associated with skeletal muscle and adipose tissue (5,10,15,19,45,58). Mice lacking A-type lamins or deficient in processing lamin A develop skeletal and cardiac muscular dystrophies, thus confirming the importance of A-type lamins for muscle differentiation and/or maintenance (52, 65). The mechanism by which mutations in A-type lamins generate tissue-specific disorders is unknown. However, one model posits that lamin A/C regulates gene expression in differentiated tissue by coordinating the activity of key transcription factors.A-type lamins localize to p...

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“…In this context, the lamina, underlying the nuclear membrane, is essential for maintaining nuclear shape, spacing nuclear pore complexes, anchoring and organizing heterochromatin [1][2][3][4]. Lamina is a meshwork of nuclear-specific type V intermediate filaments (IF) called lamins, associated with the nuclear membrane, either directly or through interactions with membrane-bound proteins [2,3,[5][6][7][8]. As a basic structural unit, lamins form coiled-coil dimers that associate longitudinally to form polar head-to-tail polymers [2,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Structures of the lamin A/C R335W and E347K mutants: Implications for dilated cardiolaminopathies

Bollati

Barbiroli

Favalli

et al. 2012

Biochemical and Biophysical Research Communications

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a b s t r a c tDilated cardiomyopathy (DCM) is a condition whereby the normal muscular function of the myocardium is altered by specific or multiple aetiologies. About 25-35% of DCM patients show familial forms of the disease, with most mutations affecting genes encoding cytoskeletal proteins. Most of the DCM-related mutations fall in the Lamin AC gene, in particular in the Coil2B domain of the encoded protein. In this context, we focussed our studies on the crystal structures of two lamin Coil2B domain mutants (R335W and E347K). Both R335 and E347 are higly conserved residues whose substitution has little effects on the Coil2B domain three-dimensional structure; we can thus hypothesize that the mutations may interfere with the binding of components within the nuclear lamina, or of nuclear factors, that have been proposed to interact/associate with lamin A/C.

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Proteins that bind A-type lamins: integrating isolated clues

Cited by 202 publications

References 91 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

Stabilization of the Retinoblastoma Protein by A-Type Nuclear Lamins Is Required for INK4A-Mediated Cell Cycle Arrest

Structures of the lamin A/C R335W and E347K mutants: Implications for dilated cardiolaminopathies

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