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Dual role of TMS1/ASC in death receptor signaling

Oncogene volume 25, pages 6948–6958 (2006)Cite this article

Abstract

Aberrant DNA methylation of promoter region CpG islands is associated with gene silencing and serves as an alternative to mutations in the inactivation of tumor suppressor genes in human cancers. We identified a gene TMS1 (for Target of Methylation-mediated Silencing) that is subject to such epigenetic silencing in a significant proportion of human breast and other cancers. Also known as ASC and PYCARD, TMS1 encodes a bipartite intracellular signaling molecule with proposed roles in apoptosis and inflammation. However, the precise role of this protein in the pathogenesis of breast and other cancers has not been clearly defined. In this study, we examined the role of TMS1/ASC in death receptor signaling. We found that TMS1/ASC is upregulated in response to treatment with TNF-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor-α (TNFα) in breast epithelial cells, but not in human fibroblasts. This upregulation was not dependent on the synthesis of a TNFα-regulated intermediate or alterations in mRNA stability, suggesting a direct effect on TMS1/ASC transcription. Induction of TMS1/ASC by TNFα was blocked by co-expression of a dominant negative IκBα, small interfering RNA-mediated knockdown of RelA/p65, or concurrent treatment with SP600125, indicating a requirement for the nuclear factor-κB (NF-κB) and jun kinase signaling pathways. Although previous work has suggested that TMS1/ASC may be directly regulated by p53, we found that whereas treatment of breast epithelial cells or normal diploid fibroblasts with DNA damaging agents resulted in the stabilization of endogenous p53 and a concomitant increase in p21, it had little impact on the expression of TMS1/ASC mRNA or protein. We further show that whereas TMS1/ASC is not required for TNFα or TRAIL-induced activation of NF-κB or caspase-8, it can promote caspase-8 activation independently of death receptor–ligand interactions. Taken together, these data suggest that upregulation of TMS1/ASC by TNFα and subsequent activation of caspase-8 could function to amplify the apoptotic signal induced by death receptors in some cell types, including breast epithelial cells.

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Acknowledgements

This work was supported by a Research Scholar Award to PMV from the American Cancer Society (RSG-02-144-01-CCG) and a predoctoral fellowship to MJP from the US Army Medical Research and Materiel Command Breast Cancer Research Program (DAMD-17-03-1-0578).

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  1. Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, GA, USA

    M J Parsons & P M Vertino

  2. Department of Radiation Oncology and the Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    P M Vertino

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Correspondence to P M Vertino.

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Parsons, M., Vertino, P. Dual role of TMS1/ASC in death receptor signaling. Oncogene 25, 6948–6958 (2006). https://doi.org/10.1038/sj.onc.1209684

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