Disease relevance of LBR

• Heterozygous mutations in LBR cause Pelger-Huët anomaly, characterized by morphologically abnormal neutrophil nuclei, and homozygous mutations cause HEM/Greenberg skeletal dysplasia, characterized by developmental abnormalities and 3 beta-hydroxysterol-epsilon-14-reductase deficiency [1].
• A fusion protein containing the amino-terminal domain of human LBR is recognized by autoantibodies from patients with primary biliary cirrhosis, and these serum antibodies label the nuclear envelope when examined by immunofluorescence microscopy [2].
• These results indicate that dissociation of HP1alpha from LBR and consequent perturbation of the nuclear envelope induced by polyomavirus Agno promote the translocation of virions out of the nucleus [3].
• Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huët anomaly [4].
• Serum immunoglobulins, salivary IgA, natural isohaemagglutinins, Fc-IgG receptor-bearing cells and suppressor T lymphocytes were absent, together with an impaired de novo DNA synthesis after PHA, Con A, PWM and Cowan I strain from Staphylococcus aureus stimulation [5].

Psychiatry related information on LBR

• This was confirmed by time studies where 1) a 2 min HIV-pretreatment followed by washing before stimulation was sufficient to inhibit PHA induced proliferation of normal lymphocytes, and 2) addition of HIV to PHA prestimulated lymphocytes failed to inhibit proliferation, e.g., there was no effect on preactivated lymphocytes [6].
• The PHA-induced calcium signal in lymphocytes is altered after blockade of K(+)-channels in Alzheimer's disease [7].
• High responders to life stress had significantly less response to PHA, and high responders to cold pressor stress had lower PWM responses [8].
• An analysis of all aphidicolin-inducible breakpoints has been carried out in PHA stimulated T-lymphocytes of five patients with classical Rett syndrome, their mothers and a group of age matched controls [9].
• The only difference in the immunological status of the patients who had experienced a stressful life event in the previous twelve months and those that had not, involved PHA mitogenic activity which was significantly lower after a stressful event [10].

High impact information on LBR

• The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane [11].
• Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43 [11].
• We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner [11].
• Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly) [11].
• During the PHA-induced transformation of resting lymphocytes, the Class I, II, and III enzyme levels rise dramatically [12].

Chemical compound and disease context of LBR

• The antiviral activity of azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI) against HIV-1 was comparatively evaluated in PHA-stimulated PBM [13].
• The percent change achieved by the addition of indomethacin to a PHA-induced proliferative response was significantly increased in patients with cirrhosis compared with controls (p less than 0.001) [14].
• Blastogen A induced peak uptake of thymidine during day 6 of tissue culture whereas PHA induced peak uptake during day 5 and tetanus during day 8 [15].
• Cell-to-cell fusion studies showed significantly attenuated fusion between freshly isolated resting T cells and T cells constitutively expressing high levels of HIV envelope glycoprotein (HXB/gpt) compared with T cells first stimulated with either PHA or OKT3 mAb [16].
• This antiserum was found to block U50,488H-mediated inhibition of 1) Staphylococcus aureus Cowen strain I-induced B and T lymphocyte proliferation, 2) PHA-induced T lymphocyte proliferation, and 3) S. aureus Cowen strain I-induced IgG production [17].

Biological context of LBR

• Both of these new LBR-like genes are on chromosome 11q13 [18].
• The TM7SF2 gene contains 10 coding exons, and its intron positions are exactly conserved in the part of the LBR gene encoding its carboxyl-terminal domain [18].
• SRPK1 and LBR protein kinases show identical substrate specificities [19].
• 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 [20].
• LBR (lamin B receptor) is an integral protein of the inner nuclear membrane encoded by a gene on human chromosome 1q42 [18].

Anatomical context of LBR

• Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization [21].
• Whereas LBR is localized to the inner nuclear membrane, these two related proteins are in the endoplasmic reticulum [18].
• LBR is sparse or undetectable in all the thyroid samples [22].
• We suggest that p56 is a sea urchin LBR homologue that targets membranes to chromatin and later anchors the membrane to the lamina [23].
• Mutations in LBR recently have been reported also to cause Pelger-Huët anomaly, an autosomal dominant trait characterized by hypolobulated nuclei and abnormal chromatin structure in granulocytes [24].

Associations of LBR with chemical compounds

• 1. LBR has a nucleoplasmic, amino-terminal domain of approximately 200 amino acids followed by a carboxyl-terminal domain similar in sequence to yeast and plant sterol reductases [18].
• To test the effects of C14 reductase inhibitors on LBR activity, we constructed EMY54, an ergosterol-requiring strain that is devoid of both sterol C8-C7 isomerase and sterol C14 reductase activities [25].
• Sterol biosynthesis and proliferation of LBR-producing cells were found to be highly susceptible to fenpropimorph and tridemorph, but only moderately susceptible to SR 31747 [25].
• The heterologous LBR was not extracted by 8 M urea, indicating that it was integrated into the membrane [26].
• Participation of multiple kinases in regulation of the binding of lamin B receptor (LBR) to chromatin was suggested previously (Takano, M., Takeuchi, M., Ito, H., Furukawa, K., Sugimoto, K., Omata, S., and Horigome, T. (2002) Eur. J. Biochem. 269, 943-953) [27].

Physical interactions of LBR

• Primary structure analysis and lamin B and DNA binding of human LBR, an integral protein of the nuclear envelope inner membrane [2].
• Antibodies against LBR also co-immunoprecipitated HP1 proteins from cell extracts [28].
• The paradigm of p18 suggests that transmembrane complexes formed by the nuclear lamins and LBR provide potential docking sites for integral membrane proteins of the nuclear envelope that equilibrate between the rough endoplasmic reticulum and the inner nuclear membrane [29].

Other interactions of LBR

• 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 [20].
• Cross-linking experiments, however, illustrate a tight association of HA95 with LBR and LAP2 only [30].
• The modular domain organization of HP1-type proteins and LBR can explain some of the diverse protein-protein interactions at the chromatin-lamina-membrane interface of the nuclear envelope [31].
• We also define a new class of variant PxVxL CSD-binding motifs in Sp100A, LBR, and ATRX [32].
• Interestingly, emerin and LBR initially accumulated at distinct, separate locations, but then became uniform 8 minutes after the onset of anaphase, concurrent with the recovery of nuclear import function [33].

Analytical, diagnostic and therapeutic context of LBR

• Immunofluorescence microscopy showed that a major population of the lamin B receptor (LBR), an inner nuclear membrane protein, was recovered in the cytoplasm in association with the ER [34].
• Cell fractionation showed the presence of the heterologous lamin B and LBR in a subnuclear fraction enriched in nuclear envelopes [26].
• Double immunoelectron microscopy showed colocalization of the heterologous lamin B and LBR in the yeast nuclear envelope and in the LBR-induced membrane stacks [26].
• The LBR amino-terminal domain precipitates lamin B from nuclear extracts and retards the migration of double-stranded DNA subjected to agarose gel electrophoresis [2].
• We show here that the chromo shadow domain mediates the self-associations of HP1-type proteins and is also necessary for binding to LBR both in vitro and in the yeast two-hybrid assay [31].

References