Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Meng, Jie; Jiang, Jing; Atsumi, Toru; Bando, Hidenori; Okuyama, Yuko; Sabharwal, Lavannya; Nakagawa, Ikuma; Higuchi, Haruka; M, Ota; Okawara, Momoko; Ishitani, Ryuichiro; Nureki, Osamu; Higo, Daisuke; Arima, Yasunobu; Ogura, Hideki; Kamimura, Daisuke; Murakami, Masaaki

doi:10.4049/jimmunol.1601082

Cited by 24 publications

(38 citation statements)

References 28 publications

(39 reference statements)

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“…Furthermore, TMEM147 molecules were associated with endogenous BCR and NF‐κB p65, but not CK2α (Figure F), and the association of BCR with NF‐κB p65 was compromised in TMEM147‐knockdown cells (Figure G). These results suggest that TMEM147 acts as a scaffold protein to bind BCR with NF‐κB p65 and is required for the downstream phosphorylation events mediated by the BCR‐CK2α–NF‐κB p65 pathway .…”

Section: Resultsmentioning

confidence: 88%

Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147–MediatedNF‐κB Activation

Tanaka

Nakagawa

et al. 2020

Arthritis & Rheumatology

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Objective. We have previously reported that the coactivation of NF-κB and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-κB target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-κB activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-κB activator in chondrocytes.Methods. Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes.Results. Samples obtained from RA patients and mouse models of RA showed coactivation of NF-κB and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-κB targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-κB complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-κB activity.Conclusion. These results suggest that chondrocytes play a role in the development of RA via TMEM147mediated NF-κB activation and indicate a novel therapeutic strategy for RA.

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Section: Resultsmentioning

confidence: 88%

Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147–MediatedNF‐κB Activation

Tanaka

Nakagawa

et al. 2020

Arthritis & Rheumatology

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“…HEK293T cells were cotransfected with pEF-BOS containing full-length wild-type (WT) or mutant Psen1, BCR, and/or CK2a cDNA. Mutant cDNAs for mouse BCR were described in our recent paper (16). Mouse Psen1 mutant cDNA lacking aa 1-73 (D1-73) or 271-376 (D271-376), in which a large part of the hydrophilic cytoplasmic loop was deleted, was prepared by an inverse PCR method using full-length Psen1 cDNA.…”

Section: Immunoprecipitationmentioning

confidence: 99%

“…1C), suggesting the function of Psen1 in the NF-kB pathway does not significantly depend on g-secretase activity. Next, to investigate whether Psen1 acts as a positive regulator of the NF-kB pathway in vivo, we employed cytokine-induced arthritis in F759 mice (7,13,14,16). Lentivirus carrying Psen1 shRNA or p65 shRNA was injected into the ankle joints of F759 mice followed by injections of IL-6 and IL-17 (coactivation of STAT3 and NF-kB) into the ankle joints to induce NF-kB-mediated arthritis development.…”

Section: Psen1 Acts As a Positive Regulator Of Nf-kb Pathway In Vitromentioning

confidence: 99%

“…We recently reported a role for the BCR gene in NF-kB activation via its formation of a complex with CK2a (16). CK2a phosphorylates p65 at a specific serine residue, 529, which establishes a binding site for histone acetyltransferase p300 (16).…”

Section: Psen1 Associates With Bcr and Ck2a To Activate Nf-kbmentioning

confidence: 99%

“…For example, we recently reported that breakpoint cluster region (BCR), which forms the oncogenic fusion protein BCR-Abl (15), is associated with the a subunit of casein kinase II (CK2a), leading to the phosphorylation of BCR at Y177 and establishment of a NF-kB p65 binding site after TNF-a stimulation (16). The binding of p65 to the BCR-CK2a complex phosphorylates serine 529 of p65, which is required for the association of p65 with p300 histone acetyltransferase, chromatin opening, and the transcription of NF-kB target genes (16). In the current study, we selected presenilin 1 (Psen1) from the aforementioned screening and investigated its role in inflammation development.…”

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Presenilin 1 Regulates NF-κB Activation via Association with Breakpoint Cluster Region and Casein Kinase II

Tanaka

Sabharwal

et al. 2018

The Journal of Immunology

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We recently reported that NF-κB-mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the γ-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR-CK2α-p65 complex to induce NF-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-secretase activity. Mechanistically, Psen1 associated with the BCR-CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α-induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR-CK2α-p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR-CK2α-p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.

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Molecular Implications of BCR-ABL1 in Hematological Malignancies

Machado,

Pessoa,

Montenegro

et al. 2024

Comprehensive Hematology and Stem Cell Research

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Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Cited by 24 publications

References 28 publications

Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147–MediatedNF‐κB Activation

Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147–MediatedNF‐κB Activation

Presenilin 1 Regulates NF-κB Activation via Association with Breakpoint Cluster Region and Casein Kinase II

Molecular Implications of BCR-ABL1 in Hematological Malignancies

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