scholarly journals Activation of COUP-TFI by a Novel Diindolylmethane Derivative

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 220 ◽  
Author(s):  
Kyungsil Yoon ◽  
Chien-Cheng Chen ◽  
Asuka Orr ◽  
Patricia Barreto ◽  
Phanourios Tamamis ◽  
...  

Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is an orphan receptor and member of the nuclear receptor superfamily. Among a series of methylene substituted diindolylmethanes (C-DIMs) containing substituted phenyl and heteroaromatic groups, we identified 1,1-bis(3′-indolyl)-1-(4-pyridyl)-methane (DIM-C-Pyr-4) as an activator of COUP-TFI. Structure activity studies with structurally diverse heteroaromatic C-DIMs showed that the pyridyl substituted compound was active and the 4-pyridyl substituent was more potent than the 2- or 3-pyridyl analogs in transactivation assays in breast cancer cells. The DIM-C-Pyr-4 activated chimeric GAL4-COUP-TFI constructs containing full length, C- or N-terminal deletions, and transactivation was inhibited by phosphatidylinositol-3-kinase and protein kinase A inhibitors. However, DIM-C-Pyr-4 also induced transactivation and interactions of COUP-TFI and steroid receptor coactivators-1 and -2 in mammalian two-hybrid assays, and ligand-induced interactions of the C-terminal region of COUP-TFI were not affected by kinase inhibitors. We also showed that DIM-C-Pyr-4 activated COUP-TFI-dependent early growth response 1 (Egr-1) expression and this response primarily involved COUP-TFI interactions with Sp3 and to a lesser extent Sp1 bound to the proximal region of the Egr-1 promoter. Modeling studies showed interactions of DIM-C-Pyr-4 within the ligand binding domain of COUP-TFI. This report is the first to identify a COUP-TFI agonist and demonstrate activation of COUP-TFI-dependent Egr-1 expression.

2012 ◽  
Vol 73 (3) ◽  
pp. 257-262 ◽  
Author(s):  
Kinzo Matsumoto ◽  
Kazuya Ono ◽  
Hirofumi Ouchi ◽  
Ryohei Tsushima ◽  
Yukihisa Murakami

Sign in / Sign up

Export Citation Format

Share Document