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- Castillejo-Lopez, Casimiro, et al.
(författare)
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Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71:1, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesAltered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis.MethodsThe GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK.ResultsEpistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies.ConclusionsThis study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.
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| 2. |
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| 3. |
- Gobl, Anders E, et al.
(författare)
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Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism
- 1999
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Ingår i: Biochimica et Biophysica Acta. - 0006-3002 .- 1878-2434. ; 1447:1, s. 51-56
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Tidskriftsartikel (refereegranskat)abstract
- Recently the multiple endocrine neoplasia type 1 (MEN-1) tumor suppressor gene was cloned. MEN-1 encodes a nuclear protein, called menin, of hitherto unknown function. In order to investigate the biological function of menin we employed the yeast two-hybrid system to identify menin-interacting proteins. Here we report that menin functions as a transcriptional repressor through interaction with the transcription factor JunD. The interaction is mediated via the N-terminal transcription activation domain of JunD, and the C-terminal part of menin. In transient co-transfection experiments, expression of menin leads to specific repression of JunD transcriptional activity, which is dependent on the integrity of the menin C-terminal region. C-Terminal truncations of the protein not only abolish repression, but increase JunD transcriptional activity, implying the existence of a functional domain separate from the JunD-binding region. Menin-mediated repression is relieved by the histone deacetylase inhibitor trichostatin A, indicating that deacetylation of histones is an essential component of this repression mechanism, as has recently been demonstrated for the retinoblastoma protein. Missense, in-frame deletions, frameshift and nonsense mutations lead to inactivation of menin or possibly to truncated proteins. This would result in loss of repression of menin/JunD target genes, as well as non-target genes through indirect mechanisms, deregulation of cellular growth control and endocrine tumorigenesis.
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| 4. |
- Lopez-Egido, Juan R., et al.
(författare)
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Differentially regulated genes in MEN1-transfected BON cells using RT-differential display and oligonucleotide microarrays
- 2009
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 29:6, s. 1859-1866
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Apart from inactivation of the MEN1 gene, the molecular mechanisms involved in tumorigenesis of the endocrine organs and MEN1-associated non-endocrine lesions remain unknown. MATERIALS AND METHODS: In order to learn more about down-stream effects upon MEN1 gene inactivation BON1 cells were transfected with a MEN1 gene construct (BON/M1C), and both RT-differential display and oligonucleotide microarrays were performed. RESULTS: Three genes (SMARCC1, OVCA2 and SRp55) found to be differentially regulated on differential display were corroborated by northern blots on cell line RNA when comparing MEN1 transfected cells with control (empty vector transfection). When comparing two different passages of BON/M1C with two passages of vector control using oligonucleotide microarrays, 25 up-regulated genes and 64 down-regulated genes could be found using a cut-off of >or=1.6 times. CONCLUSION: These findings might contribute to the understanding of the molecular pathways involved in MEN1 tumorigenesis, and may also provide knowledge of genes involved in sporadic endocrine tumorigenesis.
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