McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706, USA.
J Biol Chem. 2010 May 21;285(21):16125-34. doi: 10.1074/jbc.M110.104356. Epub 2010 Mar 30.
The two estrogen receptor (ER) subforms, ERalpha and ERbeta, are capable of forming DNA-binding homodimers and heterodimers. Although binding to DNA is thought to stabilize ER dimers, how ERalpha/alpha, ERbeta/beta, and ERalpha/beta dimerization is regulated by DNA and the chaperone protein Hsp90 is poorly understood. Using our highly optimized bioluminescence resonance energy transfer assays in conjunction with assays for transcriptional activation of ERs, we determined that DNA binding appears to play a minor role in the stabilization of ER dimers, especially in the case of ERbeta/beta homodimers. These findings suggest that ER dimers form before they associate with chromatin and that DNA binding plays a minor role in stabilizing ER dimers. Additionally, although Hsp90 is essential for the proper dimerization of ERalpha/alpha and ERalpha/beta, it is not required for the proper dimerization of ERbeta/beta. Despite this, Hsp90 is critical for the estrogen-dependent transcriptional activity of the ERbeta/beta homodimer. Thus, Hsp90 is implicated as an important regulator of distinct aspects of ERalpha and ERbeta action.
两种雌激素受体（ER）亚型，ERalpha 和 ERbeta，能够形成 DNA 结合同源二聚体和异源二聚体。尽管认为与 DNA 的结合可以稳定 ER 二聚体，但 ERalpha/alpha、ERbeta/beta 和 ERalpha/beta 二聚体如何受到 DNA 和伴侣蛋白 Hsp90 的调节还知之甚少。我们使用高度优化的生物发光共振能量转移测定法，结合 ER 转录激活的测定法，确定 DNA 结合似乎在 ER 二聚体的稳定中起次要作用，特别是在 ERbeta/beta 同源二聚体的情况下。这些发现表明 ER 二聚体在与染色质结合之前形成，并且 DNA 结合在稳定 ER 二聚体中起次要作用。此外，尽管 Hsp90 对于 ERalpha/alpha 和 ERalpha/beta 的正确二聚化是必需的，但对于 ERbeta/beta 的正确二聚化则不是必需的。尽管如此，Hsp90 对于 ERbeta/beta 同源二聚体的雌激素依赖性转录活性至关重要。因此，Hsp90 被认为是 ERalpha 和 ERbeta 作用的不同方面的重要调节剂。
