The chromosomal translocations that are closely associated with cancer, most frequently hematopoietic malignancies, disrupt master regulatory genes. Myeloid Translocation Gene Related-1 (MTGR1) is a transcriptional co-repressor that is closely related to 2 genes that are frequently disrupted by chromosomal translocations in acute myeloid leukemia, ETO (MTG8) and MTG16. In addition, LOH of MTG16 is found in up to 40% of the most common form of breast cancer and re-expression of MTG16 impairs the growth of breast cancer cell lines. Thus, the MTG family of co-repressors may function as tumor suppressors. To begin to understand the regulatory pathways that depend on this family of co-repressors, we deleted Mtgr1 from the germ line of mice. These mice are mostly normal, although they are uniformly smaller than their wild-type littermates. However, within their small intestines they have lost the majority of the cell lineage that produces Paneth, goblet, and endocrine cells. Based on this phenotype, we took a candidate approach to test whether DNA binding transcription factors that are required for the normal function of stem cells in the small intestine might recruit Mtgr1. We found that Mtgr1 associates with Tcf4, but not Math1 or Hes1. TCF4 is a DNA binding factor that mediates Wnt signaling in the small intestine. Deletion of Tcf4 in mice causes depletion of the small intestinal stem cell compartment, indicating that Tcf4 is required for stem cell self renewal. TCF4 associates with co-repressors to repress transcription, but in response to Wnt signaling beta-catenin enters the nucleus and dislodges these co-repressors to activate transcription of target genes such as c-Myc. In co-immunoprecipitation experiments Mtgr1 associated with Tcf4, but co-expression of beta-catenin impaired this association, suggesting that Mtgr1 is a negative regulator of Wnt signaling. In addition, we found that the Tcf4-regulated genes c-Myc and Id2 were expressed at higher levels in Mtgr1-null mice, consistent with a role for Mtgr1 as a co-repressor that is recruited by Tcf4. Given that the oncogenes c-Myc and Id2 are over expressed in the small intestines of Mtgr1-null mice and the association of loss of function of MTG family members in leukemia and breast cancer, we hypothesize that MTG family proteins act as tumor suppressors or genetic modifiers of tumor suppressors by negatively regulating Wnt signaling. We will directly test the role of the MTG family in tumorigenesis using a combination of in vitro and in vivo studies.
