Arbuckle N D, Dauvois S, Parker M G
Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, London, UK.
Nucleic Acids Res. 1992 Aug 11;20(15):3839-44. doi: 10.1093/nar/20.15.3839.
We have investigated the effect of a series of steroidal oestrogen antagonists, related to ICI 164,384, on the DNA binding activity of mouse oestrogen receptors expressed in insect cells. The analogues possess different side chains at the 7-position of the B ring in the steroid. Inhibition was observed when the length of the side-chain was 15-16 carbon atoms but not 10 or 20 carbon atoms and only when the 7 alpha isomer was used. The DNA binding activity of receptors expressed in COS-1 cells was also inhibited after extended periods of incubation with antioestrogens but not that of the human receptor in breast cancer cell-extracts. We have proposed that ICI 164,384 might disrupt receptor dimerisation, and therefore the variation in its ability to inhibit DNA binding activity may reflect differences in dimer stability. Since the DNA binding activity of in vitro translated receptors was inhibited when they were translated in the presence of the antioestrogen we suggest that ICI 164,384 might prevent the formation of receptor dimers without necessarily being able to disrupt preformed dimers.
我们研究了一系列与ICI 164,384相关的甾体雌激素拮抗剂对在昆虫细胞中表达的小鼠雌激素受体DNA结合活性的影响。这些类似物在甾体B环的7位具有不同的侧链。当侧链长度为15 - 16个碳原子时观察到抑制作用，而10个或20个碳原子时则没有，且仅在使用7α异构体时出现抑制。在用抗雌激素长时间孵育后，COS - 1细胞中表达的受体的DNA结合活性也受到抑制，但乳腺癌细胞提取物中的人受体的DNA结合活性未受抑制。我们提出ICI 164,384可能会破坏受体二聚化，因此其抑制DNA结合活性能力的变化可能反映了二聚体稳定性的差异。由于在抗雌激素存在下体外翻译的受体的DNA结合活性受到抑制，我们认为ICI 164,384可能会阻止受体二聚体的形成，而不一定能够破坏预先形成的二聚体。
