Interaction of beta-catenin and TIF2/GRIP1 in transcriptional activation by the androgen receptor.
The multifunctional oncoprotein beta-catenin interacts with the activation function-2 domain of androgen receptor (AR) to stimulate androgen receptor transcriptional activity, increase sensitivity, and broaden specificity of ligand interactions. beta-Catenin interacts with androgen receptor in close proximity to the binding groove for P160 coactivators such as transcriptional intermediary factor-2 (TIF2)/glucocorticoid receptor interacting protein-1 (GRIP1). beta-Catenin can also bind directly to TIF2/GRIP1. Both N- and C-terminal regions of beta-catenin are needed for optimal interaction with TIF2/GRIP1. We show that distinct residues of beta-catenin are responsible for both binding and functional interactions with androgen receptor and with TCF4, thus allowing the introduction of missense mutations that selectively affect these interactions. beta-Catenin and TIF2/GRIP1 are each able to mediate binding between the other and androgen receptor in functional interactions that enhance ligand-dependent transcription. The data strongly imply that AR, beta-catenin, and TIF2/GRIP1 bind in a three-way interaction that mediates transcription. Lastly, we observed that a beta-catenin C-terminal peptide containing 229 amino acids can bind TIF2/GRIP1 and AR but has a profound dominant inhibitory effect on ligand-dependent transcription. We propose that beta-catenin may play an integral role in formation of the androgen-receptor transcriptional complex.
Song
Liang-Nian
LN
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007-2197, USA.
Gelmann
Edward P
EP
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin