Abstract
β-Catenin is a multifunctional mediator of cellular signaling and an oncogene. Nuclear β-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 β-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 β-catenin-TCF4 complex. Overexpression of SMRT and NCoR attenuated the transcription of β-catenin-TCF4-specific reporter gene and of CCND1, an endogenous β-catenin target gene. Knockdown of endogenous SMRT or NCoR by short interfering RNA augmented the β-catenin-TCF4-mediated reporter gene expression. Glutathione S-transferase pulldown experiments showed there was a direct physical association of SMRT and NCoR with both β-catenin and TCF4. DNA-protein interaction studies revealed that the interactions between either SMRT or NCoR and β-catenin or TCF4 occurred at the promoter regions of CCND1and other target genes. These findings demonstrate an important role for corepressors SMRT and NCoR in the regulation of β-catenin-TCF4-mediated gene transcription.
Original language | English (US) |
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Pages (from-to) | 25988-25999 |
Number of pages | 12 |
Journal | Journal of Biological Chemistry |
Volume | 283 |
Issue number | 38 |
DOIs | |
State | Published - Sep 19 2008 |
Externally published | Yes |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology