Myeloid Translocation Gene Family Members Associate with T-Cell Factors (TCFs) and Influence TCF-Dependent Transcription

Abstract

Canonical Wnt signaling is mediated by a molecular "switch" that regulates the transcriptional properties of the T-cell factor (TCF) family of DNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of ␤-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited axis formation and impaired the ability of ␤-catenin and XLef-1 to induce axis duplication, indicating that MTG family members act downstream of ␤-catenin. Moreover, we found that c-Myc, a transcriptional target of the Wnt pathway, was overexpressed in the small intestines of mice lacking Mtgr1, thus linking inactivation of Mtgr1 to the activation of a potent oncogene.Canonical Wnt signaling plays a critical regulatory role in development and in stem cell functions and cellular differentiation (41, 43). Wnts initiate a signaling cascade that leads to the nuclear accumulation of ␤-catenin, which associates with T-cell factor 4 (TCF4), releasing the TCF4-associated transcriptional corepressors and recruiting coactivators to stimulate TCF4-dependent transcription. The intestinal epithelium has been a rich source of information about this pathway. For example, Tcf4 is required for small intestinal stem cell selfrenewal; mice lacking this transcription factor exhaust the capacity for continued replenishment of the epithelium in utero (24). Conversely, hyperactive Wnt signaling is closely associated with colorectal carcinoma, most commonly via inactivation of the APC tumor suppressor, which regulates the levels of ␤-catenin (41, 43). At the end point of the Wnt signaling cascade, ␤-catenin opposes the action of transcriptional corepressors for binding to TCFs to regulate genes that affect cell fate decisions.Two members of the myeloid translocation gene (MTG) family of transcriptional corepressors, MTG on chromosome 8 (MTG8; also known as ETO or RUNX1T1) and MTG on chromosome 16 (MTG16; also known as ETO2 or CBFA2T3), are disrupted by chromosomal translocations in acute myeloid leukemia (10, 29), which suggests that these factors are key regulators of cellular proliferation or differentiation. As would be expected of master regulatory factors, these targets of chromosomal translocations in acute leukemia are commonly mutated in other tumor types as well. A genomewide screen to detect mutations of genes in colorectal and breast can...

Wnt Signaling from Development to Disease: Insights from Model Systems

“…Consistent with this, TLE1 can occupy Wnt target gene chromatin in a reciprocal manner as bcat (Sierra et al 2006). Like TLEs, mouse myeloid translocation gene related-1 (Mtgr1) was recently reported to bind to TCF4 and contribute to target gene silencing (Moore et al 2008).…”

MTG16 is a tumor suppressor in colitis-associated carcinoma

“…Our long term, in vivo experiments support this conclusion. Thus, we hypothesize that MTG modulation of WNT signaling is the likely mechanism underlying MTG16's tumor-suppressive effects (32).…”

“…TOPFLASH-luciferase reporter (32) and CMV-SEAP (encoding secreted alkaline phosphatase [SEAP]) constructs were transfected into NIH 3T3 cells with sequential addition of β-catenin, TCF4, and MTG (either WT or mutant). Luciferase assay was conducted after 48 hours of transfection and luciferase levels were adjusted for transfection efficiency and viability using the SEAP values for each well.…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…In the absence of Wnt signal Lef/Tcf acts as transcriptional repressors of Wnt target genes by forming a complex with several corepressors including myeloid translocation gene related-1 (Mtgr1) (Moore et al, 2008), corepressor of Pan (Coop) (Song et al, 2010), hydrogen peroxide-inducible clone (HIC5) (Ghogomu et al, 2006;Li et al, 2011) and the most intensively studied Groucho/transducin-like enhancer of split (Gro/TLE) repressor family Chen and Courey, 2000). Upon translocation of β-catenin to nucleus Lef/Tcf factors become converted into transcriptional activators and perform expression of the target genes (Daniels and Weis, 2005).…”