The molecular basis of vitamin D receptor and beta-catenin crossregulation.
The signaling/oncogenic activity of beta-catenin can be repressed by activation of the vitamin D receptor (VDR). Conversely, high levels of beta-catenin can potentiate the transcriptional activity of 1,25-dihydroxyvitamin D3 (1,25D). We show here that the effects of beta-catenin on VDR activity are due to interaction between the activator function-2 (AF-2) domain of the VDR and C terminus of beta-catenin. Acetylation of the beta-catenin C terminus differentially regulates its ability to activate TCF or VDR-regulated promoters. Mutation of a specific residue in the AF-2 domain, which renders the VDR trancriptionally inactive in the context of classical coactivators, still allows interaction with beta-catenin and ligand-dependent activation of VDRE-containing promoters. VDR antagonists, which block the VDRE-directed activity of the VDR and recruitment of classical coactivators, do allow VDR to interact with beta-catenin, which suggests that these and perhaps other ligands would permit those functions of the VDR that involve beta-catenin interaction.
The Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC 20007, USA. ss234@georgetown.edu
Salimuddin
S
Shah
Md Naimul
MN
Islam
Sivanesan
S
Dakshanamurthy
Imran
I
Rizvi
Mahadev
M
Rao
Roger
R
Herrell
Glendon
G
Zinser
Meggan
M
Valrance
Ana
A
Aranda
Dino
D
Moras
Anthony
A
Norman
JoEllen
J
Welsh
Stephen W
SW
Byers
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D018167:Receptors, Calcitriol; D051820:TCF Transcription Factors; D051176:beta Catenin