Control of oestradiol-responsive gene regulation by oestrogen receptors (ERs) may involve complex cross-talk with retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Recently, we have shown that ERα directly interacts with RARα and RXRα through their ligand binding domains (LBDs). In the present work, we extend these results by showing that ERβ binds similarly to RARα and RXRα but not to the glucocorticoid receptor, as demonstrated by the yeast two-hybrid tests and glutathione S-transferase pull-down assays. These direct interactions were also demonstrated in gel-shift assays, in which the oestrogen response element (ERE) binding by ERα was enhanced by the RXRα LBD but was abolished by the RARα LBD. In addition, we showed that RARα and RXRα bound the ERE as efficiently as ERα, suggesting that competition for DNA binding may affect the transactivation function of the ER. In transient transfection experiments, co-expression of RARα or RXRα, along with ERα or ERβ, revealed differential modulation of the ERE-dependent transactivation, which was distinct from the results when each receptor alone was co-transfected. Importantly, when the LBD of RARα was co-expressed with ERα, transactivation of ERα on the ERE was repressed as efficiently as when wild-type RARα was co-expressed. Furthermore, liganded RARα or unliganded RXRα enhanced the ERα transactivation, suggesting the formation of transcriptionally active heterodimer complexes between the ER and retinoid receptors. Taken together, these results suggest that direct protein–protein interactions may play major roles in the determination of the biological consequences of cross-talk between ERs and RARα or RXRα.
Differential modulation of transcriptional activity of oestrogen receptors by direct protein–protein interactions with retinoid receptors
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Mi-Ryoung SONG, Soo-Kyung LEE, Young-Woo SEO, Hueng-Sik CHOI, Jae Woon LEE, Mi-Ock LEE; Differential modulation of transcriptional activity of oestrogen receptors by direct protein–protein interactions with retinoid receptors. Biochem J 15 December 1998; 336 (3): 711–717. doi: https://doi.org/10.1042/bj3360711
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