Identification of nuclear localization signals within the human BCOR protein

Surapornsawasd, Thunyaporn; Ogawa, Takuya; Moriyama, Keiji

doi:10.1016/j.febslet.2015.05.046

Cited by 8 publications

(10 citation statements)

References 20 publications

(33 reference statements)

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“…BCOR has several interacting regions in addition to BCL6, including AF9 (a region that interacts with AF9, the common mixed-lineage leukemia fusion partner), NSPC1 (a region that interacts with nervous system polycomb1), and Ankyrin (a region involved in protein-protein interaction) (Ghetu et al, 2008). The c.3668delC Mut BCOR protein Frontiers in Physiology frontiersin.org 07 (p.S12223Wfs*15) has a molecular size of 134.18 kDa and affects the AF9 region and lacks the Ankyrin region, whereas the WT BCOR has a molecular size of 188.23 kDa, as confirmed by western blot analysis in our previous study (Surapornsawasd et al, 2015). In this study, Mut BCOR failed to repress ZFPM2, the BCOR repressive target whereas WT BCOR did repress it.…”

Section: Discussionsupporting

confidence: 76%

“…A wild-type (WT) BCOR plasmid, mutated (Mut) BCOR plasmid with a c.3668delC frameshift mutation in the BCOR gene, and an empty plasmid described in our previous study were used ( Surapornsawasd et al, 2015 ). Primary human PDL fibroblasts, HPdLF (Lonza, Walkersville, MD, United States), and COS-7 cells were grown and cultured in SCGM BulletKit™ medium (Lonza) and α-MEM (Wako), respectively; they were kept in a humidified 5% CO 2 atmosphere at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Glass slides were mounted with Prolong Gold antifade reagent with DAPI (Life Technologies, Carlsbad, CA, United States), and cells were observed using a Leica AF6000 fluorescence microscope (Leica Microsystems, Wetzlar, Germany). The Flag-tagged BCOR and Mut BCOR with a frameshift mutation in c.3668delC protein were successfully detected with a monoclonal anti-FLAG M2 antibody using immunofluorescence assay and western blot analysis as described by us previously ( Surapornsawasd et al, 2015 ). Experiments were performed in triplicate to obtain reliable results.…”

Section: Methodsmentioning

confidence: 99%

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Molecular mechanism of hyperactive tooth root formation in oculo-facio-cardio-dental syndrome

Soe

Ogawa²,

Moriyama³

2022

Front. Physiol.

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Mutations in the B-cell lymphoma 6 (BCL6) interacting corepressor (BCOR) cause oculo-facio-cardio-dental (OFCD) syndrome, a rare X-linked dominant condition that includes dental radiculomegaly among other characteristics. BCOR regulates downstream genes via BCL6 as a transcriptional corepressor. However, the molecular mechanism underlying the occurrence of radiculomegaly is still unknown. Thus, this study was aimed at identifying BCOR-regulated genetic pathways in radiculomegaly. The microarray profile of affected tissues revealed that the gene-specific transcriptional factors group, wherein nucleus factor 1B, distal-less homeobox 5, and zinc finger protein multitype 2 (ZFPM2) were the most upregulated, was significantly expressed in periodontal ligament (PDL) cells of the diseased patient with a frameshift mutation (c.3668delC) in BCOR. Wild-type BCOR overexpression in human periodontal ligament fibroblasts cells significantly hampered cellular proliferation and ZFPM2 mRNA downregulation. Promoter binding assays showed that wild-type BCOR was recruited in the BCL6 binding of the ZFPM2 promoter region after immunoprecipitation, while mutant BCOR, which was the same genotype as of our patient, failed to recruit these promoter regions. Knockdown of ZFPM2 expression in mutant PDL cells significantly reduced cellular proliferation as well as mRNA expression of alkaline phosphatase, an important marker of odontoblasts and cementoblasts. Collectively, our findings suggest that BCOR mutation-induced ZFPM2 regulation via BCL6 possibly contributes to hyperactive root formation in OFCD syndrome. Clinical data from patients with rare genetic diseases may aid in furthering the understanding of the mechanism controlling the final root length.

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Section: Discussionsupporting

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular mechanism of hyperactive tooth root formation in oculo-facio-cardio-dental syndrome

Soe

Ogawa²,

Moriyama³

2022

Front. Physiol.

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“…The BCL6 co-repressor (BCOR) gene is located on chromosome Xp11.4 and encodes a transcription regulatory factor that was initially identified as an interactor partner of the germinal center-associated BCL6 protein [1,2]. The BCOR protein is located in the nucleus [3] where exerts its function as a member of the non-canonical multimeric polycomb group repressive complex 1 (PRC1) which is recruited to the target sites independently of H3K27me3 [4]. This complex is involved in the control of various biological processes, including pluripotency, reprogramming, and hematopoiesis [4,5].…”

Section: Introductionmentioning

confidence: 99%

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

et al. 2020

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Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are needed for this combinatorial AML genotype. For this purpose, we first generated a Bcor−/− knockout mouse model characterized by impaired erythroid development (macrocytosis and anemia) and enhanced thrombopoiesis, which are both features of myelodysplasia/myeloproliferative neoplasms. We then created and characterized double Bcor−/−/Dnmt3a−/− knockout mice. Interestingly, these animals developed a fully penetrant acute erythroid leukemia (AEL) characterized by leukocytosis secondary to the expansion of blasts expressing c-Kit+ and the erythroid marker Ter119, macrocytic anemia and progressive reduction of the thrombocytosis associated with loss of Bcor alone. Transcriptomic analysis of double knockout bone marrow progenitors revealed that aberrant erythroid skewing was induced by epigenetic changes affecting specific transcriptional factors (GATA1-2) and cell-cycle regulators (Mdm2, Tp53). These findings prompted us to investigate the efficacy of demethylating agents in AEL, with significant impact on progressive leukemic burden and mice overall survival. Information gained from our model expands the knowledge on the biology of AEL and may help designing new rational treatments for patients suffering from this high-risk leukemia.

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“…These other features are principally ocular (microphthalmia, cataract, glaucoma, retinal detachment), cardiac (septal defects), skeletal (hammer toes or camptodactyly, 2-3 toe syndactyly, broad halluces, radioulnar synostosis, scoliosis), and facial anomalies (cleft palate, septate nasal cartilage, long narrow face, arched eyebrows). Less freqently they include mild developmental delay (11%), posterior fossa anomalies (in a fetal loss), hearing impairment (9%) and defects of laterality (situs inversus, asplenia) in a single case (Ng, Thakker et al 2004, Horn, Chyrek et al 2005, Oberoi, Winder et al 2005, Hilton, Johnston et al 2009, Davoody, Chen et al 2012, Lozic, Ljubkovic et al 2012, Kantaputra 2014, Surapornsawasd, Ogawa et al 2015, Ma, Grigg et al 2016. In typical OFCD cases, BCOR is affected by a variety of null variants: nonsense, splicing, frameshift, deletions of part or all of the coding sequence, predicted to lead to nonsense mediated decay.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

Ragge

Isidor

Bitoun³

et al. 2018

Hum Genet

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Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.

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Identification of nuclear localization signals within the human BCOR protein

Cited by 8 publications

References 20 publications

Molecular mechanism of hyperactive tooth root formation in oculo-facio-cardio-dental syndrome

Molecular mechanism of hyperactive tooth root formation in oculo-facio-cardio-dental syndrome

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

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