Disease relevance of LMNB1

• Using a monoclonal autoantibody (72B9) derived from a murine lupus strain, we have cloned a cDNA from the human T-cell line MOLT-4, which encodes nuclear lamin B. The identity of the encoded protein as lamin B was established by both biochemical and immunological criteria [1].
• The ability of purified nuclear lamin A, lamin B, lamin C, and vimentin from Ehrlich ascites tumor cells to bind nucleic acids was investigated in vitro via a quantitative filter binding assay [2].
• Epstein-Barr virus nuclear antigen-1 colocalizes with lamin B1 in the nucleoplasm and along the nuclear rim [3].
• In the small cell lung cancer lines OH-1, OH-3, NCI-H82, NCI-H209, and NCI-H249, levels of lamin B were similar to those observed in the non-small cell lines, but the levels of lamins A and C were diminished by greater than or equal to 80% [4].
• Treatment with VES induced membrane translocation of Fas; cleavages of caspase-3, PARP, and lamin B; hypophosphorylation of retinoblastoma protein; and increase of p21(WAF1) protein level [5].

High impact information on LMNB1

• Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD [6].
• Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype [6].
• This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis [6].
• We show here that isolated peripherin binds selectively to mammalian lamin B under in vitro conditions [7].
• Network antibodies identify nuclear lamin B as a physiological attachment site for peripherin intermediate filaments [7].

Chemical compound and disease context of LMNB1

• In addition, we studied the modulatory effect of lovastatin and celecoxib on lamin B levels, caspase-3 activity and expression in relationship to apoptosis in colon cancer cell lines [8].
• METHODS: In the present study, we evaluated the prevalence of antibodies against the basement membrane antigen laminin (LMN) in patients with ANCA-associated systemic vasculitis (AASV), pathologic controls (systemic lupus erythematosus, mixed cryoglobulinaemia, Henoch-Schönlein purpura, primary glomerulonephritis) and normal individuals [9].

Biological context of LMNB1

• We found no putative disease mutations in any of these proteins in subjects with non-LMNA FPLD, but, through the screening of diseased and normal subjects, we identified several single-nucleotide polymorphisms (SNPs); specifically, five SNPs in LMNB1 and four SNPs in LBR [10].
• As LB, LAP2 and Nup153 are exposed at the inner face of the nuclear envelope and all interact with chromatin, we suggest that their cleavage allows both the detachment of NE from chromatin and the clustering of NPCs in the plane of the membrane, two conserved morphological features of apoptosis observed in this study [11].
• Deficiency in the endoproteolysis or methylation of lamin B1 results in loss of integrity and deformity of the nuclear lamina [12].
• The mammalian nuclear lamina protein lamin B1 is posttranslationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxyl-terminal CAAX motif [12].
• In vitro posttranslational modification of lamin B cloned from a human T-cell line [1].

Anatomical context of LMNB1

• Few genes have generated as much recent interest as LMNA, LMNB1 and LMNB2, which encode the components of the nuclear lamina [13].
• Lamin B1 is also almost completely absent from skeletal muscle nuclei [14].
• Lamin B incorporation and addition of new membranes are necessary for pronuclear swelling and nuclear envelope growth [15].
• Expression of the heterologous LBR, either alone or together with the heterologous lamin B, resulted in the formation of membrane stacks primarily adjacent to the nuclear envelope, but also projecting from the nuclear envelope into the cytoplasm or under the plasma membrane [16].
• Analysis of mRNA in HL60 and MOLT-4 cells, which express only lamin B, or HeLa cells, which express all three major lamins (A, B, and C), together with the comigration of in vitro-translated product with isolated HeLa cell lamin B by two-dimensional gel electrophoresis, suggests that a single lamin B is expressed in mammalian somatic cells [1].

Associations of LMNB1 with chemical compounds

• While lamin B is cleaved by caspase 6, the protease responsible for the cleavage of LAP2 and Nup153 was probably caspase 3, since (1) cleavage of both proteins was specifically prevented by in vivo addition of caspase 3 inhibitor Ac-DEVD-CHO and (2) consensus sites for these caspases are present in both proteins [11].
• The heterologous lamin B was extracted at 8 M urea, but not at 4 M urea, thus behaving as a peripheral membrane protein and indistinguishable from assembled lamins [16].
• Inspection of the deduced amino acid sequence of lamin B revealed the presence in coil 1B of the alpha-helical domain of a leucine heptad repeat region [1].
• In vitro translation with the cDNA clone revealed an EDTA-sensitive posttranslational modification which resulted in an increase in the apparent molecular weight to that equivalent to the native in vivo-synthesized lamin B protein [1].
• By monitoring intracellular expression of vimentin and lamin B1 during SA, we found that these two proteins were cleaved and that such cleavage was reversed by the pan caspase inhibitor N-benzyloxy-carbonyl-V-A-D-O-methylfluoromethyl ketone (z-VAD-fmk) [17].

Physical interactions of LMNB1

• Primary structure analysis and lamin B and DNA binding of human LBR, an integral protein of the nuclear envelope inner membrane [18].
• Lamin B bound only oligo and poly(dG); no other nucleic acids tested were bound or could compete with the binding of oligo(dG) [2].
• Lamin B-containing vesicles appear to dock on vimentin intermediate filaments during prometaphase, but dissociate from the cytoskeleton and assemble around chromatin at later phases of mitosis [19].
• Lamina-associated polypeptide 2 (LAP2) is an integral membrane protein of the inner nuclear membrane that binds to both lamin B and chromatin and has a putative role in nuclear envelope (NE) organization [20].
• The possibility of PKC-beta(II) being an apoptotic lamin kinase in these cells was further suggested by lamin B1-bound PKC-delta being inactive or only slightly active and by PKC-alpha not combining with the lamin [21].

Co-localisations of LMNB1

• A second domain sufficient to bind HA95 colocalizes with the lamin B-binding domain of LAP2beta at residues 299-373 [22].

Regulatory relationships of LMNB1

• The protease responsible appears to be calcium-dependent and the concomitant cleavage of PARP and p53 was consistent with a beta-lap-mediated activation of calpain. beta-Lap exposure also stimulated the cleavage of lamin B, a putative caspase 6 substrate [23].
• Bcl-2 prevents CD95 (Fas/APO-1)-induced degradation of lamin B and poly(ADP-ribose) polymerase and restores the NF-kappaB signaling pathway [24].
• Effector caspases such as caspase-3 are transiently activated through the mitochondrial pathway during erythroblast differentiation and cleave proteins involved in nucleus integrity (lamin B) and chromatin condensation (acinus)without inducing cell death and cleavage of GATA-1 [25].

Other interactions of LMNB1

• Among the candidate genes to consider for the non-LMNA-associated forms of FPLD are other components of the inner nuclear membrane, such as lamin B1 and B2 and the lamin B receptor [10].
• In contrast, the amount of emerin and lamin B appeared unaltered [26].
• They are encoded by three genes, LMNA, LMNB1 and LMNB2 [27].
• A carboxyl-terminal interaction of lamin B1 is dependent on the CAAX endoprotease Rce1 and carboxymethylation [12].
• Here we investigate the involvement of two proposed human mitotic lamin kinases, beta II protein kinase C (PKC) and p34cdc2/cyclin B kinase, in human lamin B1 phosphorylation in vitro and in intact cells [28].

Analytical, diagnostic and therapeutic context of LMNB1

• Lamin B was demonstrated in ELCS by immunoelectron microscopy with colloidal gold-labeled antibody [29].
• Cell fractionation showed the presence of the heterologous lamin B and LBR in a subnuclear fraction enriched in nuclear envelopes [16].
• The LBR amino-terminal domain precipitates lamin B from nuclear extracts and retards the migration of double-stranded DNA subjected to agarose gel electrophoresis [18].
• 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 [30].
• Comparison of polyadenylated RNA from NCI-H249 and NCI-H249rasH cells on Northern blots revealed similar levels of the mRNA for lamin B but higher levels of the mRNAs for lamins A and C in the v-rasH-expressing cell line [4].

References