TC1 (C8orf4) Enhances the Wnt/β-Catenin Pathway by Relieving Antagonistic Activity of Chibby

Abstract

The Wnt/B-catenin pathway has been implicated in human cancers. Here, we show that TC1 (C8orf4), a small protein present in vertebrates, functions as a positive regulator of the pathway. TC1 interacts with Chibby (Cby) and thereby enhances the signaling pathway by relieving the antagonistic function of Cby on the B-catenin-mediated transcription. Upon coexpression in mammalian cells, TC1 redistributes from nucleolus to nuclear speckles, where it colocalizes with Cby. TC1 upregulates the expression of B-catenin target genes that are implicated in invasiveness and aggressive behavior of cancers, such as metalloproteinases, laminin ;2, and others. Our data indicate that TC1 is a novel upstream regulator of the Wnt/Bcatenin pathway that enhances aggressive behavior of cancers. (Cancer Res 2006; 66(2): 723-8)

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…This increase in tumor invasion is likely mediated by the upregulation of Wnt transcriptional targets, such as EphA2 (erythropoietin-producing hepatocellular) and membrane type 3 matrix metalloproteinase (MT3-MMP) genes [199,200] . Furthermore, evidence provided by Kim et al [201,202] suggests that TC1 (C8orf4), which is upregulated in high-grade gastric cancers, coordinates the upregulation of Wnt/b-catenin target genes involved in the aggressive biological behavior and poor clinical outcome observed in advanced gastric cancer [202,203] . TC1 enhances the signaling pathway by relieving the antagonistic regulation of Chibby (Cby) on b-cateninmediated transcription [203] .…”

“…Furthermore, evidence provided by Kim et al [201,202] suggests that TC1 (C8orf4), which is upregulated in high-grade gastric cancers, coordinates the upregulation of Wnt/b-catenin target genes involved in the aggressive biological behavior and poor clinical outcome observed in advanced gastric cancer [202,203] . TC1 enhances the signaling pathway by relieving the antagonistic regulation of Chibby (Cby) on b-cateninmediated transcription [203] . Cby was first identified as an interactor with b-catenin in humans, which suggested it could be a tumor suppressor gene [204] .…”

The NBPF Gene Family

“…It was shown that the coiled-coil region in the N-terminal domain of NBPF interacts with the coiled-coil region in the C-terminal domain of Cby. This C-terminal portion of Cby harbours not only the binding site for NBPF, but also the binding site for most other known interaction partners of Cby, such as β-catenin (Takemaru et al, 2003), polycystin-2 (Hidaka et al, 2004) and TC1 (Jung et al, 2006). Functional analysis of the interaction showed that NBPF did not influence Cby-mediated Wnt signalling, nor did it compete with β-catenin binding to Cby.…”

TC1 (C8orf4) is involved in ERK1/2 pathway-regulated G1- to S-phase transition

“…TC1 (C8orf4), with the highest conservation across species focused on the ORF, was first identified in papillary thyroid carcinoma and encodes a nucleus-localized protein (1,2). The structural characterization of the TC1 protein indicates that it belongs to an increasingly large group of proteins known to be "natively unfolded" and which are believed to perform pivotal functions in the areas of cell cycle control as well as transcriptional and translational regulation (3,4).…”

“…For instance, TC1 is upregulated by IL-beta and/or TNF-alpha, and enhances the proliferation of the human FDC-like line HK, implying that TC1 is involved in linking local inflammation to the immune response (7). Additionally, through relieving the antagonistic activity of Chibby, TC1 is a positive regulator of the Wnt/beta-catenin signaling pathway which has been widely studied in the regulation of the proliferation of cancer cells (2,6,8,9). However, the exact molecular mechanism of TC1 regulating cell proliferation is still unknown and warrants extensive studies.…”