Silencing mediator for retinoid and thyroid hormone receptor and nuclear receptor corepressor attenuate transcriptional activation by the beta-catenin-TCF4 complex.

beta-Catenin is a multifunctional mediator of cellular signaling and an oncogene. Nuclear beta-catenin, when complexed with members of the T-cell factor (TCF)/leukocyte enhancer factor family of DNA-binding proteins, mediates transcriptional activation important for embryonic development and adult cell homeostasis. Deregulation of intracellular levels of beta-catenin is an early event in the development of a variety of cancers. We observed that the proteins silencing mediator for retinoid and thyroid hormone receptor (SMRT) and the nuclear receptor corepressor (NCoR) are negative regulators of transcription induced by the beta-catenin-TCF4 complex. Overexpression of SMRT and NCoR attenuated the transcription of beta-catenin-TCF4-specific reporter gene and of CCND1, an endogenous beta-catenin target gene. Knockdown of endogenous SMRT or NCoR by short interfering RNA augmented the beta-catenin-TCF4-mediated reporter gene expression. Glutathione S-transferase pulldown experiments showed there was a direct physical association of SMRT and NCoR with both beta-catenin and TCF4. DNA-protein interaction studies revealed that the interactions between either SMRT or NCoR and beta-catenin or TCF4 occurred at the promoter regions of CCND1 and other target genes. These findings demonstrate an important role for corepressors SMRT and NCoR in the regulation of beta-catenin-TCF4-mediated gene transcription.