Tzameli Iphigenia, Chua Steven S, Cheskis Boris, Moore David D
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Nucl Recept. 2003 Jun 6;1(1):2. doi: 10.1186/1478-1336-1-2.
CAR/RXR heterodimers bind a variety of hormone response elements and activate transcription in the absence of added ligands. This constitutive activity of murine CAR can be inhibited by the inverse agonist ligand androstanol or increased by the agonist TCPOBOP. RXR agonists activate some RXR heterodimer complexes, which are termed permissive, while other non-permissive complexes are not responsive to such ligands. RESULTS: Direct protein-protein interaction studies demonstrate that the RXR agonist 9-cis-RA increases interaction of CAR/RXR heterodimers with the coactivator SRC-3, but also inhibits the ability of TCPOBOP to increase and androstanol to decrease coactivator binding. CAR transactivation of a response element with a five nucleotide spacer (DR-5) is unaffected by 9-cis-RA or the synthetic RXR agonist LG1069. In agreement with the inhibitory effect observed in vitro, these rexinoids block both the TCPOBOP mediated transactivation of this element and the androstanol dependent inhibition. In contrast, CAR transactivation of other response elements is increased by rexinoids. Stable expression of CAR in a HepG2 derived cell line increases expression of the endogenous CAR target CYP2B6. This expression is further increased by TCPOBOP but decreased by either androstanol or LG1069, and LG1069 blocks the stimulatory effect of TCPOBOP but not the inhibitory effect of androstanol. CONCLUSION: We conclude that CAR/RXR heterodimers are neither strictly permissive nor non-permissive for RXR signaling. Instead, rexinoids have distinct effects in different contexts. These results expand the potential regulatory mechanisms of rexinoids and suggest that such compounds may have complex and variable effects on xenobiotic responses.
CAR/RXR异二聚体可结合多种激素反应元件，并在无添加配体的情况下激活转录。小鼠CAR的这种组成型活性可被反向激动剂配体雄甾烷醇抑制，或被激动剂TCPOBOP增强。RXR激动剂可激活一些RXR异二聚体复合物，这些复合物被称为允许性复合物，而其他非允许性复合物对这类配体无反应。结果：直接的蛋白质-蛋白质相互作用研究表明，RXR激动剂9-顺式视黄酸可增加CAR/RXR异二聚体与共激活因子SRC-3的相互作用，但也会抑制TCPOBOP增强以及雄甾烷醇降低共激活因子结合的能力。具有五个核苷酸间隔区（DR-5）的反应元件的CAR反式激活不受9-顺式视黄酸或合成RXR激动剂LG1069的影响。与体外观察到的抑制作用一致，这些视黄酸类化合物可阻断该元件的TCPOBOP介导的反式激活以及雄甾烷醇依赖性抑制。相比之下，视黄酸类化合物可增加CAR对其他反应元件的反式激活。CAR在源自HepG2的细胞系中的稳定表达可增加内源性CAR靶标CYP2B6的表达。TCPOBOP可进一步增加该表达，但雄甾烷醇或LG1069可使其降低，并且LG1069可阻断TCPOBOP的刺激作用，但不能阻断雄甾烷醇的抑制作用。结论：我们得出结论，CAR/RXR异二聚体对RXR信号传导既不是严格允许性的也不是非允许性的。相反，视黄酸类化合物在不同情况下具有不同的作用。这些结果扩展了视黄酸类化合物的潜在调节机制，并表明这类化合物可能对异生素反应具有复杂且可变的影响。
