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TCF/LEFs and Wnt signaling in the nucleus.

ABSTRACT: T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors are the major end point mediators of Wnt/Wingless signaling throughout metazoans. TCF/LEFs are multifunctional proteins that use their sequence-specific DNA-binding and context-dependent interactions to specify which genes will be regulated by Wnts. Much of the work to define their actions has focused on their ability to repress target gene expression when Wnt signals are absent and to recruit ?-catenin to target genes for activation when Wnts are present. Recent advances have highlighted how these on/off actions are regulated by Wnt signals and stabilized ?-catenin. In contrast to invertebrates, which typically contain one TCF/LEF protein that can both activate and repress Wnt targets, gene duplication and isoform complexity of the family in vertebrates have led to specialization, in which individual TCF/LEF isoforms have distinct activities.

SUBMITTER: Cadigan KM

PROVIDER: S-EPMC3536346 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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TCF/LEFs and Wnt signaling in the nucleus.

Cadigan Ken M KM Waterman Marian L ML

Cold Spring Harbor perspectives in biology 20121101 11

T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors are the major end point mediators of Wnt/Wingless signaling throughout metazoans. TCF/LEFs are multifunctional proteins that use their sequence-specific DNA-binding and context-dependent interactions to specify which genes will be regulated by Wnts. Much of the work to define their actions has focused on their ability to repress target gene expression when Wnt signals are absent and to recruit β-catenin to target genes for ac ...[more]

PMID: 23024173

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Project description:INTRODUCTION: Increased expression of the proinflammatory cytokine TNF-? in intervertebral discs (IVDs) leads to inflammation, which results in progressive IVD degeneration. We have previously reported that activation of Wnt-?-catenin (hereafter called Wnt) signaling suppresses the proliferation of nucleus pulposus cells and induces cell senescence, suggesting that Wnt signaling triggers the process of degeneration of the IVD. However, it is not known whether cross talk between TNF-? and Wnt signaling plays a role in the regulation of nucleus pulposus cells. The goal of the present study was to examine the effect of the interaction between Wnt signaling and the proinflammatory cytokine TNF-? in nucleus pulposus cells. METHODS: Cells isolated from rat nucleus pulposus regions of IVDs were cultured in monolayers, and the expression and promoter activity of Wnt signaling and TNF-? were evaluated. We also examined whether the inhibition of Wnt signaling using cotransfection with Dickkopf (DKK) isoforms and Sclerostin (SOST) could block the effects of pathological TNF-? expression in nucleus pulposus cells. RESULTS: TNF-? stimulated the expression and promoter activity of Wnt signaling in nucleus pulposus cells. In addition, the activation of Wnt signaling by 6-bromoindirubin-3'-oxime (BIO), which is a selective inhibitor of glycogen synthase kinase 3 (GSK-3) activity that activates Wnt signaling, increased TNF-? expression and promoter activity. Conversely, the suppression of TNF-? promoter activity using a ?-catenin small interfering RNA was evident. Moreover, transfection with DKK-3, DKK-4, or SOST, which are inhibitors of Wnt signaling, blocked Wnt signaling-mediated TNF-? activation; these effects were not observed for DKK-1 or DKK-2. CONCLUSIONS: Here, we have demonstrated that Wnt signaling regulates TNF-? and that Wnt signaling and TNF-? form a positive-feedback loop in nucleus pulposus cells. The results of the present study provide in vitro evidence that activation of Wnt signaling upregulates the TNF-? expression and might cause the degeneration of nucleus pulposus cells. We speculate that blocking this pathway might protect nucleus pulposus cells against degeneration.

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TCF/LEFs and Wnt signaling in the nucleus.

Publications

TCF/LEFs and Wnt signaling in the nucleus.

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