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At least 19 recordsLinked to original sources
PubMed1990

Differential effect of pH on solubilization of nuclear lamins A/C and lamin B.

Extraction of isolated rat liver nuclear envelopes with 4M urea at various pH values led to differential solubilization of lamin polypeptides. All three lamins A, B and C were solubilized to 70-80% when extraction was performed at pH 8 while only 50-60% of lamins A and C were solubilized at pH 6, leaving lamin B completely insoluble. These results indicated that the interaction of lamin B with the nuclear envelope was strongly dependent upon the ionization state of lamin B and/or of its putative attachment site.

Animals↗
PubMed2004

Formation of nuclear splicing factor compartments is independent of lamins A/C.

Nuclear lamins are major architectural elements of the mammalian cell nucleus, and they have been implicated in the functional organization of the nuclear interior, possibly by providing structural support for nuclear compartments. Colocalization studies have suggested a structural role for lamins in the formation and maintenance of pre-mRNA splicing factor compartments. Here, we have directly tested this hypothesis by analysis of embryonic fibroblasts from knock-out mice lacking A- and C-type lamins. We show that the morphology and cellular properties of splicing factor compartments are independent of A- and C-type lamins. Genetic loss of lamins A/C has no effect on the cellular distribution of several pre-mRNA splicing factors and does not affect the compartment morphology as examined by light and electron microscopy. The association of splicing factors with the nuclear matrix fraction persists in the absence of lamins A/C. Live cell microscopy demonstrates that the intranuclear positional stability of splicing factor compartments is maintained and that the exchange dynamics of SF2/ASF between the compartments and the nucleoplasm is not affected by loss of lamin A/C. Our results demonstrate that formation and maintenance of intranuclear splicing factor compartments is independent of lamins A/C, and they argue against an essential structural role of lamins A/C in splicing factor compartment morphology.

Animals↗
PubMed2000

DNase I hypersensitive sites and transcriptional activation of the lamin A/C gene.

The lamin A/C gene encodes subtypes of nuclear lamins, which are involved in nuclear envelope formation, and was recently identified as the responsible gene for the autosomal dominant Emery-Dreifuss muscular dystrophy. Expression of the lamin A/C gene is developmentally regulated but little is known about the regulatory mechanism. Previous studies of lamin A/C expression suggested that the chromatin structure is important for the regulation of its expression. To elucidate the regulatory mechanism of the lamin A/C gene expression, we have analysed the functional region of the mouse lamin A/C promoter and the chromatin structure of the gene in terms of nucleosome structure and DNase I hypersensitivity. Our analyses revealed disruption of the nucleosome array at the promoter region and the presence of multiple DNase I hypersensitive sites (HSs) which were specifically associated with expression of the lamin A/C gene. Inclusion of a segment which contained the HSs in a lamin A/C promoter-luciferase reporter plasmid showed no effect on the transfected promoter activity in transient expression assays. On the other hand, substantial enhancement of the promoter activity was detected when the transfected DNA was stably integrated into the genome, suggesting the importance of the HSs in the regulation of lamin A/C expression.

Deoxyribonuclease I↗
PubMed1999

Neuronal differentiation of NT2/D1 teratocarcinoma cells is accompanied by a loss of lamin A/C expression and an increase in lamin B1 expression.

Nuclear lamins are prominent elements of the nuclear matrix and are expressed in cell type-specific and differentiation state-specific patterns. A few observations have indicated that nervous tissue may display unusual patterns of lamin expression, in that some neurons appear to lack A-type lamins, which are generally prominently expressed in terminally differentiated, postmitotic cells. To investigate lamin expression patterns during the differentiation of a teratocarcinoma cell line into neurons, NT2/D1 cells were induced to differentiate with retinoic acid treatment. Lamin expression and organization during differentiation in vitro were examined by quantitative immunofluorescence and immunoblotting methods. Undifferentiated NT2/D1 cells were all strongly labeled with an anti-lamin B1 antibody, but displayed marked variation in A/C lamin immunoreactivity. After differentiation, neuronal nuclear envelopes were significantly more strongly labeled by anti-lamin B1 antibody than those of undifferentiated cells, but completely lacked A/C lamin immunoreactivity. In contrast, nonneuronal cells displayed a slight reduction in B1 lamin immunoreactivity, along with a distinct increase in A/C lamin levels. The loss of lamin A/C expression in NT2/D1 neurons is contrary to the pattern normally observed in most somatic cell types during early development and indicates that the nuclear matrix of some neurons, along with certain neuroendocrine and hematopoietic cells, is uniquely specialized in this regard.

Cell Differentiation↗
PubMed2005

The nuclear membrane and mechanotransduction: impaired nuclear mechanics and mechanotransduction in lamin A/C deficient cells.

Mutations in the lamin A/C gene cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Hutchinson-Gilford progeria syndrome. The tissue specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. Lamin A/C deficient fibroblasts were subjected to mechanical strain to measure nuclear mechanical properties and strain-induced signalling. We found that lamin A/C deficient fibroblasts are characterized by impaired nuclear mechanics and mechanotransduction, reflected by increased nuclear deformations, increased nuclear fragility, attenuated expression of mechanosensitive genes, and impaired transcriptional activation, leading to impaired viability of mechanically strained cells. Lamins and other nuclear envelope proteins can thus affect several levels of the mechanotransduction cascade, altering nuclear and cytoskeletal mechanics as well as playing an important role in mechanically activated gene regulation. Individual mutations in the lamin A/C gene could potentially selectively interfere with any of these functions, explaining the tissue-specific effects observed in the laminopathies.

Animals↗
PubMed2001

Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of missense mutations in lamin a/c gene.

The lamin A/C (LMNA) gene has recently been reported to be mutated in familial partial lipodystrophy, Dunnigan variety (FPLD). We found mutations within exon 8 of LMNA (R482Q, R482W, and G465D) in 12 families with typical FPLD and in exon 11 (R582H) in 1 atypical family. To investigate phenotypic heterogeneity, we compared body fat distribution, using anthropometry and whole body magnetic resonance imaging, and metabolic parameters in women with atypical and typical FPLD. Compared with women with typical FPLD, the two sisters with atypical FPLD had less severe loss of sc fat from all the extremities and trunk and particularly from the gluteal region and medial parts of proximal thighs. Both types had similar excess of fat deposition in the neck, face, intraabdominal, and intermuscular regions. Women with atypical FPLD tended to have lower serum triglyceride and higher high density lipoprotein cholesterol concentrations. As exon 11 of LMNA does not comprise part of the lamin C-coding region, the R582H mutation affects only lamin A protein. Therefore, a unique phenotype of atypical FPLD may result from disrupted interaction of lamin A with other proteins and chromatin compared with typical FPLD, in which interaction of both lamins A and C may be disrupted.

Adipose Tissue↗
PubMed2006

Age-related changes in lamin A/C expression in the osteoarticular system: laminopathies as a potential new aging mechanism.

BACKGROUND: Mutations in lamin A/C have been described as associated to severe changes in bone and joints. In this study we hypothesize that the expression of lamin A/C may play a role in the pathogenesis of age-related diseases in the osteoarticular system. METHODOLOGY: C57BL/6 young and old mice (4 months; n=10 and 24 months; n=10) were sacrificed. Limbs were isolated for histopathological and Western blot analysis. The proportion of cells (osteoblasts and chondrocytes) positive for lamin A/C was quantified by immunohistochemistry. Lamin B1 was used as control. Finally, lamin A/C expression in bone marrow cells was quantified by Western blot. RESULTS: A significant reduction in lamin A/C was found in osteoblasts of old as compared to young mice (42% versus 76%, p<0.001). Interestingly, lamin A/C but not lamin B1 expression was found in bone matrix with higher levels in young bone. Additionally, a significant reduction in the number of lamin A/C expressing chondrocytes was seen in old mice as compared to young mice (32% versus 84%, p<0.001). Finally, a reduction in lamin A/C expression was found in bone marrow cells obtained from old mice as compared to young mice. CONCLUSION: This is the first assessment of the age-related changes in lamin A/C expression in the osteoarticular system. We conclude that with aging there is a reduction in lamin A/C expression which could have a significance on osteoarticular cells function and viability.

Aging↗
PubMed2005

HIV protease inhibitors block adipocyte differentiation independently of lamin A/C.

OBJECTIVES: To determine the importance of lamin A/C for fat cell differentiation in vitro and for the anti-adipogenic activity of HIV protease inhibitors such as indinavir. METHODS: Lipodystrophy-associated and processing-defective mutants of lamin A were stably expressed at high levels in 3T3-L1 pre-adipocytes. Additionally, 3T3-L1 pre-adipocytes with stable reduction of lamin A/C or emerin were derived. The cells were differentiated for 8 days into mature adipocytes in the presence or absence of indinavir or nelfinavir. RESULTS: 3T3-L1 cells stably expressing high levels of lipodystrophy-associated or processing-defective mutants of lamin A differentiated with comparable efficiencies to control cells. Similarly, cells with dramatically reduced lamin A levels differentiated as efficiently as controls. Although indinavir stimulated the accumulation of unprocessed lamin A, cells with dramatically reduced lamin A/C levels and no detectable prelamin A remained responsive to an indinavir-induced inhibition of adipogenesis. CONCLUSIONS: The ability of HIV protease inhibitor to stimulate the accumulation of unprocessed lamin A is neither necessary nor sufficient to explain their anti-adipogenic activity. Furthermore, lamin A/C plays a minimal role in the differentiation of 3T3-L1.

Adipocytes↗
PubMed2004

Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.

Mutations in the lamin A/C gene (LMNA) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. The tissue-specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle-specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. To investigate the role of lamin A/C in mechanotransduction, we subjected lamin A/C-deficient mouse embryo fibroblasts to mechanical strain and measured nuclear mechanical properties and strain-induced signaling. We found that Lmna-/- cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-kappaB-regulated transcription in response to mechanical or cytokine stimulation was attenuated in Lmna-/- cells despite increased transcription factor binding. Lamin A/C deficiency is thus associated with both defective nuclear mechanics and impaired mechanically activated gene transcription. These findings suggest that the tissue-specific effects of lamin A/C mutations observed in the laminopathies may arise from varying degrees of impaired nuclear mechanics and transcriptional activation.

Animals↗
PubMed1997

Expression of nuclear lamins in human tissues and cancer cell lines and transcription from the promoters of the lamin A/C and B1 genes.

We have examined the expression of lamins A, B1, and C in human tissues and cancer cell lines and the function of the lamin A/C and B1 gene promoters in transfected cells. Northern analysis and immunoblotting demonstrated that lamin A/C mRNA and protein were not detectable in some human cell lines whereas lamin B1 was always present. Sequencing of approximately 2.6 kb of the lamin A/C and 1.6 kb of the lamin B1 genes 5' to the translation initiation sites showed that they did not contain typical TATA boxes near the transcription start sites. The lamin B1 and A/C proximal promoter regions were transcribed in transfected HeLa, Raji, and NT2/D1 cell lines even if the cells did not contain detectable endogenous lamin A/C mRNA or protein. These results show that, similar to most cytoplasmic intermediate filament genes, transcriptional regulatory elements in the promoters of the human nuclear lamin A/C and B1 genes do not control their cell type-specific expression in culture lines.

Base Sequence↗
PubMed1990

Induction of nuclear lamins A/C in macrophages in in vitro cultures of rat bone marrow precursor cells and human blood monocytes, and in macrophages elicited in vivo by thioglycollate stimulation.

Hemopoietic cells from blood and bone marrow of mammals usually do not express lamins A/C but only lamin B, and this feature distinguishes these cells from the vast majority of somatic cells of the adult animal, which reveal lamins A/C as well as lamin B. Here we have cultivated rat bone marrow precursor cells and human monocytes isolated from peripheral blood in tissue culture supplemented with certain growth factors. These conditions allow bone marrow precursor cells and monocytes to differentiate almost quantitatively into accessory cells and/or mature macrophages. The different cell types in the cultures can be identified both morphologically and by other assays. Antibodies specific for mouse A/C lamins, human A/C lamins, or B lamins have been used to define the lamin complement as a function of time in culture and of cell type. A dramatic increase in lamin A/C-positive cells was observed in the first 3 days of culture with both accessory cells and macrophages expressing lamins A/C as soon as such cell types could be identified. Parallel in vivo experiments showed that treatment with thioglycollate caused the percentage of lamin A/C-positive peritoneal macrophages to increase from 5 to 80% between Days 0 and 6.

Animals↗
PubMed2000

Identification of a novel retinoic acid-responsive element within the lamin A/C promoter.

A-type lamins are not present in either early embryos or the embryonal carcinoma (EC) cell line. P19 cells, which are EC cell line, are able to express A-type lamins upon retinoic acid (RA) treatment. Here we report that a novel RA-responsive element, termed lamin A/C-RA-responsive element (L-RARE), is located within the lamin A/C promoter. RA activated the luciferase activity of the reporter which had four tandem repeats of the wild-type L-RARE, while a loss of function mutant, which altered CACCCCC to CACtatC within L-RARE, did not respond. Four specific binding complexes of L-RARE, Complexes-A, -B, -C, and -D, were detected in protein extracts obtained from P19 cells treated with and without RA. Specific antibodies revealed that Sp1 and Sp3 were included in Complex-A and Complexes-B and -C, respectively. Thus, L-RARE was important in the RA-mediated activation of the lamin A/C promoter and was recognized by DNA binding proteins.

Animals↗
PubMed2002

Myne-1, a spectrin repeat transmembrane protein of the myocyte inner nuclear membrane, interacts with lamin A/C.

Mutations in the genes encoding the inner nuclear membrane proteins lamin A/C and emerin produce cardiomyopathy and muscular dystrophy in humans and mice. The mechanism by which these broadly expressed gene products result in tissue-specific dysfunction is not known. We have identified a protein of the inner nuclear membrane that is highly expressed in striated and smooth muscle. This protein, myne-1 (myocyte nuclear envelope), is predicted to have seven spectrin repeats, an interrupted LEM domain and a single transmembrane domain at its C-terminus. We found that myne-1 is expressed upon early muscle differentiation in multiple intranuclear foci concomitant with lamin A/C expression. In mature muscle, myne-1 and lamin A/C are perfectly colocalized, although colocalization with emerin is only partial. Moreover, we show that myne-1 and lamin A/C coimmunoprecipitate from differentiated muscle in vitro. The muscle-specific inner nuclear envelope expression of myne-1, along with its interaction with lamin A/C, indicates that this gene is a potential mediator of cardiomyopathy and muscular dystrophy.

Amino Acid Sequence↗
PubMed2004

Silencing lamin A/C in human endometrial stromal cells: a model to investigate endometrial gene function and regulation.

Silencing of a target mRNA by small interfering RNA (siRNA) has emerged as a new and powerful tool to study gene function, and post-transcriptional gene silencing can now be accomplished with 21-23 nucleotide RNA that mediate sequence-specific mRNA degradation. In the current study we employed lamin A/C siRNA to silence lamin A/C expression in cultured human endometrial stromal cells and investigated downstream cellular markers for proof of concept. Human endometrial stromal cells from three subjects were transfected with lamin A/C siRNA or non-silencing fluorescein-labelled siRNA, and flow cytometric analysis revealed 95-98% transfection efficiency after 6 h of treatment. RT-PCR and quantitative RT-PCR were used to measure mRNA degradation of lamin A/C, and 75-88% silencing was observed 48 h post-transfection. Western blotting and immunocytochemistry confirmed corresponding decrease in lamin A/C protein within 48 h of gene silencing. The downstream effect of lamin A/C silencing was investigated by immunocytochemical analysis of the cellular localization of the protein, emerin, an important component of the nuclear lamina and known to be regulated by lamin expression. Marked displacement of emerin from the nuclear lamina to the cytoplasm was observed when lamin A/C was silenced in human endometrial stromal cells, confirming functional silencing of lamin A/C resulting in a nuclear lamina assembly defect. Silencing target mRNA by siRNA in human endometrial stromal cells can be more broadly applied to investigate the function and regulation of other genes in this cell type, and the methodology and data presented herein strongly support the more widespread use of this powerful tool in endometrial biology research.

Adult↗
PubMed2006

Lamin A/C assembly defects in Emery-Dreifuss muscular dystrophy can be regulated by culture medium composition.

Emery-Dreifuss muscular dystrophy results from mutations in either emerin or lamin A/C and is caused by loss of some unknown function of emerin-lamin A/C complexes. This function must be of special importance in the skeletal and cardiac muscles that are affected by the disease. Some lamin A/C mutant proteins form 'nuclear foci' in the nucleoplasm when overexpressed by transient transfection and similar aggregates have been seen in cultured skin fibroblasts from patients with Emery-Dreifuss muscular dystrophy, suggesting that mis-assembly of the A-type lamina may be involved in the pathogenesis. Whereas an earlier study of cultured skin fibroblasts compared several different missense mutations in lamin A/C, we have chosen to study one particular Emery-Dreifuss mutation (R249Q) in greater detail. We found that the proportion of fibroblast nuclei containing abnormal lamin A/C aggregates can vary from 0.5 to 23.6% depending on the culture conditions. In particular, switching from a 'slow growth' medium to 'rapid growth' media increased both the number and size of nuclear aggregates. Similar results were obtained with fibroblasts from a second unrelated patient with the same mutation. In contrast to these aggregates of endogenous lamin A/C, 'nuclear foci' formed after transfection of mouse embryo fibroblasts by mutant lamin A/C were not affected by culture conditions. Faulty assembly of the nuclear lamina by mutated lamin A/C molecules could be partly responsible for the disease phenotype, though this has not been proven. The present study suggests that inappropriate lamin A/C assembly may be preventable by manipulation of cell growth conditions.

Adult↗
PubMed2001

Distinct changes in intranuclear lamin A/C organization during myoblast differentiation.

Intranuclear lamin foci or speckles have been observed in various cell types. In order to explore the possibility of changes in internal lamin organization during muscle differentiation, we have examined the appearance of A-type lamin speckles that associate with RNA splicing factor speckles in C2C12 myoblasts and myotubes. Lamin speckles were observed in dividing myoblasts but disappeared early during the course of differentiation in postmitotic myocytes, and were absent in myotubes and muscle fibers. However, no changes were seen in the typical peripheral organization of lamins A/C or B1 or in RNA splicing factor speckles. Lamin speckles were also absent in quiescent myoblasts but reappeared as cells were reactivated to enter the cell cycle. These changes were not observed in other quiescent cell types. Immunoblot analysis indicated that the abundance and migration of lamins A and C was not altered in differentiated myoblasts. When myotube or quiescent myoblast nuclei were extracted with nucleases and detergent, a uniformly stained internal lamina was revealed, indicating that lamins A/C were antigenically masked in these cells, probably owing to structural reorganization of the lamina during differentiation or quiescence. Our results suggest that muscle cell differentiation is accompanied by regulated rearrangements in the organization of the A-type lamins.

Animals↗
PubMed2002

Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene.

Mutations in different domains of the LMNA (lamin A/C) gene encoding nuclear envelope proteins lamin A and lamin C cause familial partial lipodystrophy (Dunnigan variety), dilated cardiomyopathy, and autosomal dominant forms of Emery-Dreifuss and limb-girdle muscular dystrophies. The objective of this study was to evaluate LMNA variants in two families with familial partial lipodystrophy (Dunnigan variety) who also had cardiac conduction system defects and other manifestations related to cardiomyopathy. We performed mutational analysis of the lamin A/C gene in affected and unaffected subjects by deoxyribonucleic acid sequencing of the exons. Two novel missense mutations were identified in exon 1 of the lamin A/C gene. One mutation, R28W (CGG-->TGG), affected the amino-terminal head domain, and the other, R62G (CGC-->GGC), affected the alpha-helical rod domain. Affected subjects from both families had an increased prevalence of cardiac manifestations, such as atrioventricular conduction defects, atrial fibrillation, and heart failure due to ventricular dilatation, as well as pacemaker implantation. The proband from one of the families also had proximal muscle weakness. Novel genetic defects in the LMNA gene in two families with the Dunnigan variety of familial partial lipodystrophy, cardiac conduction system defects, and other manifestations related to cardiomyopathy suggest the occurrence of a multisystem dystrophy syndrome due to LMNA mutations.

Adult↗
PubMed2005

Inactivation of the lamin A/C gene by CpG island promoter hypermethylation in hematologic malignancies, and its association with poor survival in nodal diffuse large B-cell lymphoma.

PURPOSE: Lamins support the nuclear envelope and provide anchorage sites for chromatin, but they are also involved in DNA synthesis, transcription, and apoptosis. Although the lack of expression of A-type lamins in lymphoma and leukemia has been reported, the mechanism was unknown. We investigated the possible role of CpG island hypermethylation in lamin A/C silencing and its prognostic relevance. PATIENTS AND METHODS: The promoter CpG island methylation status of the lamin A/C gene, encoding the A-type lamins, was analyzed by bisulfite genomic sequencing and methylation-specific polymerase chain reaction in human cancer cell lines (n = 74; from 17 tumor types), and primary leukemias (n = 60) and lymphomas (n = 80). Lamin A/C expression was determined by reverse-transcription polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. RESULTS: seven (50%) of 14 leukemia- and five (42%) of 13 lymphoma cell lines. The presence of hypermethylation was associated with the loss of gene expression while a demethylating agent restored expression. In primary malignancies, lamin A/C hypermethylation was present in 18% (nine of 50) of acute lymphoblastic leukemias and 34% (14 of 41) of nodal diffuse large B-cell lymphomas. The presence of lamin A/C hypermethylation in nodal diffuse large B-cell lymphomas correlated strongly with a decrease in failure-free survival (Kaplan-Meier, P = .0001) and overall survival (Kaplan-Meier, P = .0005). CONCLUSION: Epigenetic silencing of the lamin A/C gene by CpG island promoter hypermethylation is responsible for the loss of expression of A-type lamins in leukemias and lymphomas. The finding that lamin A/C hypermethylation is associated with poor outcome in diffuse large B-cell lymphomas suggests important clinical implications.

Antimetabolites, Antineoplastic↗