Stabilized β-Catenin Extends Thymocyte Survival by Up-Regulating Bcl-xL

Xie, Huimin; Huang, Zhaofeng; Sadim, Maureen; Sun, Zuoming

doi:10.4049/jimmunol.175.12.7981

Cited by 81 publications

(101 citation statements)

References 40 publications

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“…Previously we have shown that transgenic expression of stabilized ␤-catenin (␤-cat Tg ) protects CD4 ϩ CD8 ϩ thymocytes from spontaneous apoptosis by specifically up-regulating Bcl-x L in this subset of thymocytes (16). These results were consistent with the role of TCF-1 in the survival of the CD4 ϩ CD8 ϩ thymocytes (17,18).…”

supporting

confidence: 79%

“…tg mice used in this study have been previously described (16). Mice were housed at the specific pathogen-free animal facility of the Biological Resource Laboratory of the University of Illinois at Chicago, following university guidelines.…”

Section: ␤-Catmentioning

confidence: 99%

“…Tg mice were previously generated in our laboratory by targeting a stabilized ␤-catenin to the T cell compartments by a CD4 promoter (16). To further elucidate the role of transgenic ␤-catenin in the activation-induced deletion of peripheral T cells in vivo, WT…”

Section: ␤-Catmentioning

confidence: 99%

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Stabilized β-Catenin Potentiates Fas-Mediated T Cell Apoptosis

Huang

Wang

Xie

et al. 2008

The Journal of Immunology

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In response to Ag stimulation, Ag-specific T cells proliferate and accumulate in the peripheral lymphoid tissues. To avoid excessive T cell accumulation, the immune system has developed mechanisms to delete clonally expanded T cells. Fas/FasL-mediated apoptosis plays a critical role in the deletion of activated peripheral T cells, which is clearly demonstrated by superantigen (staphylococcal enterotoxin B)-induced deletion of Vβ8+ T cells. Using transgenic mice expressing a stabilized β-catenin (β-catTg), we show here that β-catenin was able to enhance apoptosis of activated T cells by up-regulating Fas. In response to staphylococcal enterotoxin B stimulation, β-catTg mice exhibited accelerated deletion of CD4+Vβ8+ T cells compared with wild type mice. Surface Fas levels were significantly higher on activated T cells obtained from β-catTg mice than that from wild type mice. Additionally, T cells from β-catTg mice were more sensitive to apoptosis induced by crosslinking Fas, activation-induced cell death, and to apoptosis induced by cytokine withdrawal. Lastly, β-catenin bound to and stimulated the Fas promoter. Therefore, our data demonstrated that the β-catenin pathway was able to promote the apoptosis of activated T cells in part via up-regulation of Fas.

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supporting

confidence: 79%

Section: ␤-Catmentioning

confidence: 99%

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Stabilized β-Catenin Potentiates Fas-Mediated T Cell Apoptosis

Huang

Wang

Xie

et al. 2008

The Journal of Immunology

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“…4D). β-catenin has been shown to directly activate the expression of Bcl-xL (45,47,48), and we found that Bcl-xL is a critical downstream mediator of the addiction to β-catenin in MYC-induced lymphomas. The phenotypic consequences of β-catenin inhibition may be explained by an "oncogenic shock" model, in which the rapid loss of survival cues such as Bcl-xL and the persistence of proapoptotic signaling results in an imbalance that favors cell death (49).…”

Section: Discussionmentioning

confidence: 76%

Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

Choi

Felsher

2014

Proc. Natl. Acad. Sci. U.S.A.

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Many cancers exhibit sensitivity to the inhibition of a single genetic lesion, a property that has been successfully exploited with oncogene-targeted therapeutics. However, inhibition of single oncogenes often fails to result in sustained tumor regression due to the emergence of therapy-resistant cells. Here, we report that MYC-driven lymphomas frequently acquire activating mutations in β-catenin, including a previously unreported mutation in a splice acceptor site. Tumors with these genetic lesions are highly dependent on β-catenin for their survival and the suppression of β-catenin resulted in marked apoptosis causally related to a decrease in Bcl-xL expression. Using a novel inducible inhibitor of β-catenin, we illustrate that, although MYC withdrawal or β-catenin inhibition alone results in initial tumor regression, most tumors ultimately recurred, mimicking the clinical response to single-agent targeted therapy. Importantly, the simultaneous combined inhibition of both MYC and β-catenin promoted more rapid tumor regression and successfully prevented tumor recurrence. Hence, we demonstrated that MYC-induced tumors are addicted to mutant β-catenin, and the combined inactivation of MYC and β-catenin induces sustained tumor regression. Our results provide a proof of principle that targeting multiple oncogene addicted pathways can prevent therapeutic resistance.oncogene addiction | combination targeted therapy | splice site mutations

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“…This result confirmed a critical role of CnA␤ in T cell activation. To determine whether cell death contributed to the significantly reduced [ 3 H]thymidine incorporation by CnA␤ Ϫ/Ϫ T cells, we performed a apoptosis assay using annexin V and 7-aminoactinomycin D as described previously (16,23,24). We first analyzed apoptosis of the CD4 ϩ T cells obtained from WT and (Fig.…”

Section: ϫ/ϫ T Cells Undergo Accelerated Spontaneous Apoptosismentioning

confidence: 99%

Requirement of Calcineurin Aβ for the Survival of Naive T Cells

Manicassamy

Gupta

Huang

et al. 2008

The Journal of Immunology

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Calcineurin (Cn) is a Ca2+/calmodulin-dependent phosphatase that dephosphorylates and activates NFAT, a transcription factor essential for T cell activation. T lymphocytes predominantly express the calcineurin Aβ (CnAβ) isoform, and the deletion of the CnAβ gene results in defective T cell proliferation and IL-2 production in response to TCR stimulation. In this study, we show that CnAβ enhances the spontaneous survival of naive T cells by maintaining high levels of Bcl-2, a critical homeostatic survival factor for naive T cells. T cells obtained from CnAβ−/− mice displayed accelerated spontaneous apoptosis. The observed apoptosis of the CnAβ−/− T cells was prevented by IL-7 and IL-15, two cytokines critical for the homeostatic survival of naive T cells. Furthermore, CD4+ or CD8+ single positive CnAβ−/− thymocytes also underwent accelerated apoptosis. However, no obvious difference in the apoptosis of CD4+CD8+ double positive thymocytes was observed between CnAβ−/− and wild-type mice, suggesting a specific function of CnAβ in the survival of single positive T cells. Bcl-2 levels were found to be significantly lower in CnAβ−/− T cells. Transgenic expression of Bcl-xL restored the survival of the CnAβ−/− T cells. Thus, in addition to its role in mediating TCR signals essential for T cell activation, CnAβ is also required for the homeostatic survival of naive T cells.

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Stabilized β-Catenin Extends Thymocyte Survival by Up-Regulating Bcl-xL

Cited by 81 publications

References 40 publications

Stabilized β-Catenin Potentiates Fas-Mediated T Cell Apoptosis

Stabilized β-Catenin Potentiates Fas-Mediated T Cell Apoptosis

Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

Requirement of Calcineurin Aβ for the Survival of Naive T Cells

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