The B-cell tumor promoter Bcl-3 suppresses inflammation-associated colon tumorigenesis in epithelial cells

Tang, Wanhu; Wang, Hongshan; Ha, Hojin; Tassi, Ilaria; Bhardwaj, Reetika; Claudio, Estefanı́a; Siebenlist, Ulrich

doi:10.1038/onc.2016.152

Cited by 14 publications

(8 citation statements)

References 34 publications

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“…Histology of DSS-treated colon was scored by a combination of inflammatory cell infiltration (score 0-3) and tissue damage (score 0-3) as previously described. 34 Littermate controls were used in all experiments.…”

Section: Cd3-specific Antibody and Dss Treatmentsmentioning

confidence: 99%

Bcl‐3 suppresses differentiation of RORγt⁺ regulatory T cells

Tang

Saret

Tian

et al. 2021

Immunol. Cell Biol.

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Regulatory T cells (Tregs) exert inhibitory function under various physiological conditions and adopt diverse characteristics following environmental cues. Multiple subsets of Tregs expressing master transcription factors of helper T cells such as RORct, T-bet, Gata3 and PPARc have been characterized, but the molecular mechanism governing the differentiation of these subsets remains largely unknown. Here we report that the atypical IjB protein family member Bcl-3 suppresses RORct + Treg accumulation. The suppressive effect of Bcl-3 was particularly evident in the mouse immune tolerance model of anti-CD3 therapy. Using conditional knockout mice, we illustrate that loss of Bcl-3 specifically in Tregs was sufficient to boost RORct + Treg formation and resistance of mice to dextran sulfate sodium-induced colitis. We further demonstrate the suppressive effect of Bcl-3 on RORct + Treg differentiation in vitro. Our results reveal a novel role of nuclear factor-kappa B signaling pathways in Treg subset differentiation that may have clinical implications in immunotherapy.Bcl-3 suppresses RORct + Tregs W Tang et al.

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Section: Cd3-specific Antibody and Dss Treatmentsmentioning

confidence: 99%

Bcl‐3 suppresses differentiation of RORγt⁺ regulatory T cells

Tang

Saret

Tian

et al. 2021

Immunol. Cell Biol.

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“…18 Finally, Bcl-3 suppresses inflammation-associated colon tumorigenesis in epithelial cells by dampening tumorigenic NF-κB signaling. 19 Moreover, previously uncovered evidence demonstrated the function of Bcl-3 in pluripotency maintenance. Bcl-3 functions as a downstream molecule of LIF/STAT3 signaling and positively regulates pluripotency genes, including Oct4, Sox2, and Nanog, in mouse embryonic stem cells (mESCs).…”

Section: Introductionmentioning

confidence: 99%

Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer

Chen

Wang

Jiang

et al. 2020

Sig Transduct Target Ther

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Wnt/β-catenin signaling plays a critical role in colorectal cancer (CRC) tumorigenesis and the homeostasis of colorectal cancer stem cells (CSCs), but its molecular mechanism remains unclear. B-cell lymphoma 3 (Bcl-3), a member of the IκB family, is overexpressed in CRC and promotes tumorigenicity. Here, we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/β-catenin signaling. Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/β-catenin signaling. Moreover, our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential for β-catenin transcriptional activity in CRC cells. Interestingly, Wnt3a increases the level and nuclear translocation of Bcl-3, which binds directly to β-catenin and enhances the acetylation of β-catenin at lysine 49 (Ac-K49-β-catenin) and transcriptional activity. Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups from β-catenin, thus interrupting Wnt/β-catenin activity. In CRC clinical specimens, Bcl-3 expression negatively correlates with the overall survival of CRC patients. A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-β-catenin. Collectively, our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-β-catenin, which serves as a promising therapeutic target for CRC.

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“…6D). Since Tnfα is critical for lupus‐like phenotypes in lpr mice and Bcl‐3 negatively regulates the Tnfα signaling pathways [29], we hypothesized that suppression of Tnfα signaling may be critical for the inhibitory function of Bcl‐3 in restraining autoimmunity in lpr mice. We, thus, generated Bcl‐3, Fas, and Tnfα triple deficient mice, and found that loss of Tnfα attenuated splenomegaly in Bcl3 −/− / lpr mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Bcl‐3 inhibits lupus‐like phenotypes in BL6/lpr mice

et al. 2020

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Bcl‐3 is an atypical member of the IκB family that modulates NF‐κB activity in nuclei. lpr mice carry the lpr mutation in Fas, resulting in functional loss of this death receptor; they serve as models for lupus erythematosus and autoimmune lymphoproliferation syndrome (ALPS). To explore the biologic roles of Bcl‐3 in this disease model, we generated BL6/lpr mice lacking Bcl‐3. Unlike lpr mice on an MRL background, BL6/lpr mice present with very mild lupus‐ or ALPS‐like phenotypes. Bcl‐3 KO BL6/lpr mice, however, developed severe splenomegaly, dramatically increased numbers of double negative T cells — a hallmark of human lupus, ALPS, and MRL/lpr mice — and exhibited inflammation in multiple organs, despite low levels of autoantibodies, similar to those in BL6/lpr mice. Loss of Bcl‐3 specifically in T cells exacerbated select lupus‐like phenotypes, specifically organ infiltration. Mechanistically, elevated levels of Tnfα in Bcl‐3 KO BL6/lpr mice may promote lupus‐like phenotypes, since loss of Tnfα in these mice reversed the pathology due to loss of Bcl‐3. Contrary to the inhibitory functions of Bcl‐3 revealed here, this regulator has also been shown to promote inflammation in different settings. Our findings highlight the profound, yet highly context‐dependent roles of Bcl‐3 in the development of inflammation‐associated pathology.

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The B-cell tumor promoter Bcl-3 suppresses inflammation-associated colon tumorigenesis in epithelial cells

Cited by 14 publications

References 34 publications

Bcl‐3 suppresses differentiation of RORγt⁺ regulatory T cells

Bcl‐3 suppresses differentiation of RORγt⁺ regulatory T cells

Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer

Bcl‐3 inhibits lupus‐like phenotypes in BL6/lpr mice

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The B-cell tumor promoter Bcl-3 suppresses inflammation-associated colon tumorigenesis in epithelial cells

Cited by 14 publications

References 34 publications

Bcl‐3 suppresses differentiation of RORγt+ regulatory T cells

Bcl‐3 suppresses differentiation of RORγt+ regulatory T cells

Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer

Bcl‐3 inhibits lupus‐like phenotypes in BL6/lpr mice

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Bcl‐3 suppresses differentiation of RORγt⁺ regulatory T cells

Bcl‐3 suppresses differentiation of RORγt⁺ regulatory T cells