Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

“…Fig 6A and 6B show that a ten-fold lower concentration of UAB110 (0.2 μM) resulted in 1680 (1306+7+2+19+346) upregulated DEGs and 1162 (824+9+68+4+23+234) downregulated DEGs, in agreement with the previously reported higher potency of UAB110 [ 15 ]. A subset of 905 DEGs was shared between UAB30 and UAB110-treated samples ( S1 Table ), with the rest of the DEGs being unique for each rexinoid.…”

“…Critical evidence in support of the role of RXRα in mediating the increase in ATRA signaling came from the measurements of ATRA concentration in rexinoid-treated dnRXRα-rafts versus EV-rafts. Consistent with our previous report [ 15 ], ATRA concentration in EV-rafts rose nearly 2-fold and 4.5-fold upon treatment with UAB30 and UAB110, respectively; however, no significant increase in ATRA concentration was detected in rexinoid-treated dnRXRα-rafts. Thus, the AF-2 domain of RXRα was necessary for mediating the rexinoid-induced rise in ATRA concentration and signaling.…”

“…The effects of UAB30 and UAB110 on histology of EV-raft were consistent with our previously published studies [ 14 , 15 ], with increased proliferation of basal cells and reduced thickness of granular and cornified layers. In contrast, these effects of UAB30 and UAB110 were significantly diminished in dnRXRα-rafts.…”

“…Treatment of EV-rafts with 2 μM UAB30 increased ATRA concentration to 6.32 ± 1.60 pmol/g tissue, whereas 0.2 μM UAB110 raised ATRA to 15.22 ± 1.92 pmol/g of tissue. These results were consistent with our previously reported effects of UAB rexinoids on ATRA levels in skin rafts [15].…”

“…One of the questions remaining in the field is how specific rexinoid actions are and to what degree RXR protein is required for that. As we have shown previously, in organotypic skin epidermis, UAB30 and UAB110 rexinoids preferentially activate the RXR-RAR signaling pathway, resulting in increased levels of ATRA [ 14 , 15 ]. Here, we investigated whether RXRα is necessary for mediating the increase in ATRA concentration and signaling.…”

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

“…Fig 6A and 6B show that a ten-fold lower concentration of UAB110 (0.2 μM) resulted in 1680 (1306+7+2+19+346) upregulated DEGs and 1162 (824+9+68+4+23+234) downregulated DEGs, in agreement with the previously reported higher potency of UAB110 [ 15 ]. A subset of 905 DEGs was shared between UAB30 and UAB110-treated samples ( S1 Table ), with the rest of the DEGs being unique for each rexinoid.…”

“…Critical evidence in support of the role of RXRα in mediating the increase in ATRA signaling came from the measurements of ATRA concentration in rexinoid-treated dnRXRα-rafts versus EV-rafts. Consistent with our previous report [ 15 ], ATRA concentration in EV-rafts rose nearly 2-fold and 4.5-fold upon treatment with UAB30 and UAB110, respectively; however, no significant increase in ATRA concentration was detected in rexinoid-treated dnRXRα-rafts. Thus, the AF-2 domain of RXRα was necessary for mediating the rexinoid-induced rise in ATRA concentration and signaling.…”

“…The effects of UAB30 and UAB110 on histology of EV-raft were consistent with our previously published studies [ 14 , 15 ], with increased proliferation of basal cells and reduced thickness of granular and cornified layers. In contrast, these effects of UAB30 and UAB110 were significantly diminished in dnRXRα-rafts.…”

“…Treatment of EV-rafts with 2 μM UAB30 increased ATRA concentration to 6.32 ± 1.60 pmol/g tissue, whereas 0.2 μM UAB110 raised ATRA to 15.22 ± 1.92 pmol/g of tissue. These results were consistent with our previously reported effects of UAB rexinoids on ATRA levels in skin rafts [15].…”

“…One of the questions remaining in the field is how specific rexinoid actions are and to what degree RXR protein is required for that. As we have shown previously, in organotypic skin epidermis, UAB30 and UAB110 rexinoids preferentially activate the RXR-RAR signaling pathway, resulting in increased levels of ATRA [ 14 , 15 ]. Here, we investigated whether RXRα is necessary for mediating the increase in ATRA concentration and signaling.…”

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

“…Fig 6A and 6B show that a ten-fold lower concentration of UAB110 (0.2 μM) resulted in 1680 (1306+7+2+19+346) upregulated DEGs and 1162 (824+9+68+4+23+234) downregulated DEGs, in agreement with the previously reported higher potency of UAB110 [ 15 ]. A subset of 905 DEGs was shared between UAB30 and UAB110-treated samples ( S1 Table ), with the rest of the DEGs being unique for each rexinoid.…”

“…Critical evidence in support of the role of RXRα in mediating the increase in ATRA signaling came from the measurements of ATRA concentration in rexinoid-treated dnRXRα-rafts versus EV-rafts. Consistent with our previous report [ 15 ], ATRA concentration in EV-rafts rose nearly 2-fold and 4.5-fold upon treatment with UAB30 and UAB110, respectively; however, no significant increase in ATRA concentration was detected in rexinoid-treated dnRXRα-rafts. Thus, the AF-2 domain of RXRα was necessary for mediating the rexinoid-induced rise in ATRA concentration and signaling.…”

“…The effects of UAB30 and UAB110 on histology of EV-raft were consistent with our previously published studies [ 14 , 15 ], with increased proliferation of basal cells and reduced thickness of granular and cornified layers. In contrast, these effects of UAB30 and UAB110 were significantly diminished in dnRXRα-rafts.…”

“…Treatment of EV-rafts with 2 μM UAB30 increased ATRA concentration to 6.32 ± 1.60 pmol/g tissue, whereas 0.2 μM UAB110 raised ATRA to 15.22 ± 1.92 pmol/g of tissue. These results were consistent with our previously reported effects of UAB rexinoids on ATRA levels in skin rafts [15].…”

“…One of the questions remaining in the field is how specific rexinoid actions are and to what degree RXR protein is required for that. As we have shown previously, in organotypic skin epidermis, UAB30 and UAB110 rexinoids preferentially activate the RXR-RAR signaling pathway, resulting in increased levels of ATRA [ 14 , 15 ]. Here, we investigated whether RXRα is necessary for mediating the increase in ATRA concentration and signaling.…”

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

“…Fig 6A and 6B show that a ten-fold lower concentration of UAB110 (0.2 μM) resulted in 1680 (1306+7+2+19+346) upregulated DEGs and 1162 (824+9+68+4+23+234) downregulated DEGs, in agreement with the previously reported higher potency of UAB110 [ 15 ]. A subset of 905 DEGs was shared between UAB30 and UAB110-treated samples ( S1 Table ), with the rest of the DEGs being unique for each rexinoid.…”

“…Critical evidence in support of the role of RXRα in mediating the increase in ATRA signaling came from the measurements of ATRA concentration in rexinoid-treated dnRXRα-rafts versus EV-rafts. Consistent with our previous report [ 15 ], ATRA concentration in EV-rafts rose nearly 2-fold and 4.5-fold upon treatment with UAB30 and UAB110, respectively; however, no significant increase in ATRA concentration was detected in rexinoid-treated dnRXRα-rafts. Thus, the AF-2 domain of RXRα was necessary for mediating the rexinoid-induced rise in ATRA concentration and signaling.…”

“…The effects of UAB30 and UAB110 on histology of EV-raft were consistent with our previously published studies [ 14 , 15 ], with increased proliferation of basal cells and reduced thickness of granular and cornified layers. In contrast, these effects of UAB30 and UAB110 were significantly diminished in dnRXRα-rafts.…”

“…Treatment of EV-rafts with 2 μM UAB30 increased ATRA concentration to 6.32 ± 1.60 pmol/g tissue, whereas 0.2 μM UAB110 raised ATRA to 15.22 ± 1.92 pmol/g of tissue. These results were consistent with our previously reported effects of UAB rexinoids on ATRA levels in skin rafts [15].…”

“…One of the questions remaining in the field is how specific rexinoid actions are and to what degree RXR protein is required for that. As we have shown previously, in organotypic skin epidermis, UAB30 and UAB110 rexinoids preferentially activate the RXR-RAR signaling pathway, resulting in increased levels of ATRA [ 14 , 15 ]. Here, we investigated whether RXRα is necessary for mediating the increase in ATRA concentration and signaling.…”