Role of GAC63 in transcriptional activation mediated by beta-catenin.
Beta-catenin is a key mediator in the canonical Wnt signaling pathway, which plays important roles in multiple developmental processes. Inappropriate activation of this pathway leads to developmental defects and development of certain cancers. Upon Wnt signaling, beta-catenin binds TCF/LEF transcription factors. The TCF/LEF-beta-catenin complex then recruits a variety of transcriptional coactivators to the promoter/enhancer region of Wnt-responsive genes and activates target gene transcription. In this article, we demonstrate that GRIP1-associated coactivator 63 (GAC63), a recently identified nuclear receptor (NR) coactivator, interacts with beta-catenin. The N-terminus of GAC63 is the binding site for beta-catenin, whereas a C-terminal fragment of beta-catenin including armadillo repeats 10-12 binds to GAC63. Over-expression of GAC63 enhanced the transcriptional activity of beta-catenin, and also greatly enhanced TCF/LEF-regulated reporter gene activity in a beta-catenin-dependent manner. Endogenous GAC63 was recruited to TCF/LEF-responsive enhancer elements when beta-catenin levels were induced by LiCl. In addition, reduction of endogenous GAC63 level by small interfering RNA (siRNA) inhibited TCF/LEF-mediated gene transcription. Our findings reveal a new function of GAC63 in transcriptional activation of Wnt-responsive genes.
Chen
Yong-Heng
YH
Department of Pathology, University of Southern California, Los Angeles, California 90089, USA.
Yang
Catherine K
CK
Xia
Meng
M
Ou
Chen-Yin
CY
Stallcup
Michael R
MR
D000818:Animals; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D014157:Transcription Factors; D015533:Transcriptional Activation; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D009687:Nuclear Proteins; C120900:SLC30A9 protein, human; D014157:Transcription Factors; D051176:beta Catenin; D018021:Lithium Chloride