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A critical role for the regulated wnt-myc pathway in naive T cell survival.

ABSTRACT: Wnt signaling is involved in T cell development, activation, and differentiation. However, the role for Wnt signaling in mature naive T cells has not been investigated. In this article, we report that activation of Wnt signaling in T cell lineages by deletion of the Apc (adenomatous polyposis coli) gene causes spontaneous T cell activation and severe T cell lymphopenia. The lymphopenia is the result of rapid apoptosis of newly exported, mature T cells in the periphery and is not due to defects in thymocyte development or emigration. Using chimera mice consisting of both wild-type and Apc-deficient T cells, we found that loss of naive T cells is due to T cell intrinsic dysregulation of Wnt signaling. Because Apc deletion causes overexpression of the Wnt target gene cMyc, we generated mice with combined deletion of the cMyc gene. Because combined deletion of cMyc and Apc attenuated T cell loss, cMyc overexpression is partially responsible for spontaneous T cell apoptosis and lymphopenia. Cumulatively, our data reveal a missing link between Wnt signaling and survival of naive T cells.

SUBMITTER: Wong C

PROVIDER: S-EPMC4272883 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A critical role for the regulated wnt-myc pathway in naive T cell survival.

Wong Chunshu C Chen Chong C Wu Qi Q Liu Yang Y Zheng Pan P

Journal of immunology (Baltimore, Md. : 1950) 20141126 1

Wnt signaling is involved in T cell development, activation, and differentiation. However, the role for Wnt signaling in mature naive T cells has not been investigated. In this article, we report that activation of Wnt signaling in T cell lineages by deletion of the Apc (adenomatous polyposis coli) gene causes spontaneous T cell activation and severe T cell lymphopenia. The lymphopenia is the result of rapid apoptosis of newly exported, mature T cells in the periphery and is not due to defects i ...[more]

PMID: 25429066

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Project description:BackgroundWhile regulated WNT activity is required for normal development and stem cell maintenance, mutations that lead to constitutive activation of the WNT pathway cause cellular transformation and drive colorectal cancer. Activation of the WNT pathway ultimately leads to the nuclear translocation of β-catenin which, in complex with TCF/LEF factors, promotes the transcription of genes necessary for growth. The proto-oncogene MYC is one of the most critical genes activated downstream the WNT pathway in colon cancer. Here, we investigate the converse regulation of the WNT pathway by MYC.MethodsWe performed RNA-seq analyses to identify genes regulated in cells expressing MYC. We validated the regulation of genes in the WNT pathway including LEF1 by MYC using RT-qPCR, Western blotting, and ChIP-seq. We investigated the importance of LEF1 for the viability of MYC-expressing cells in in fibroblasts, epithelial cells, and colon cells. Bioinformatic analyses were utilized to define the expression of MYC-regulated genes in human colon cancer and metabolomics analyses were used to identify pathways regulated by LEF1 in MYC expressing cells.ResultsMYC regulates the levels of numerous WNT-related genes, including the β-catenin co-transcription factor LEF1. MYC activates the transcription of LEF1 and is required for LEF1 expression in colon cancer cells and in primary colonic cells transformed by APC loss of function, a common mutation in colon cancer patients. LEF1 caused the retention of β-catenin in the nucleus, leading to the activation of the WNT pathway in MYC-expressing cells. Consequently, MYC-expressing cells were sensitive to LEF1 inhibition. Moreover, we describe two examples of genes induced in MYC-expressing cells that require LEF1 activity: the peroxisome proliferator activated receptor delta (PPARδ) and the Acyl CoA dehydrogenase 9 (ACAD9).ConclusionsWe demonstrated that MYC is a transcriptional regulator of LEF1 in colonic cells. Our work proposes a novel pathway by which MYC regulates proliferation through activating LEF1 expression which in turn activates the WNT pathway.

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A critical role for the regulated wnt-myc pathway in naive T cell survival.

Publications

A critical role for the regulated wnt-myc pathway in naive T cell survival.

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