Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Mol Cell Endocrinol. 2012 Jan 2;348(1):331-8. doi: 10.1016/j.mce.2011.09.032. Epub 2011 Sep 22.
Nuclear estrogen receptor α (ERα) regulates target gene expression in response to ligands through two distinct mechanisms: direct binding to DNA and indirect tethering through other DNA-bound transcription factors, such as AP-1. In the studies described herein, we examined the molecular mechanisms underlying the activation of ERα in the AP-1 tethering pathway by the selective estrogen receptor modulator (SERM) raloxifene (Ral). Our results with the MMP1 and PRUNE genes indicate that the c-Fos component of the AP-1 tethering factor and the c-Jun N-terminal kinase 1 (JNK1) are constitutively bound at the promoter regions prior to Ral exposure. Ral then promotes the binding of ERα at the promoter in a c-Fos-dependent manner. Interestingly, we found that JNK1 enzymatic activity is required for Ral-dependent gene activation through ERα. Our results suggest that one role for Ral-dependent recruitment of ERα to the AP-1 binding site is to stimulate JNK1 enzymatic activity. Alternatively, Ral-occupied ERα might recruit protein substrates to promoter-bound JNK1 without any change in JNK1 activity. Collectively, our studies have revealed a new role for JNK1 in determining gene regulatory outcomes by ERα.
核雌激素受体 α（ERα）通过两种不同的机制响应配体调节靶基因表达：直接与 DNA 结合和通过其他与 DNA 结合的转录因子（如 AP-1）间接连接。在本文描述的研究中，我们研究了选择性雌激素受体调节剂（SERM）raloxifene（Ral）在 AP-1 连接因子中激活 ERα 的分子机制。我们对 MMP1 和 PRUNE 基因的研究表明，AP-1 连接因子的 c-Fos 成分和 c-Jun N-末端激酶 1（JNK1）在 Ral 暴露之前就已在启动子区域持续结合。然后，Ral 以 c-Fos 依赖的方式促进 ERα 在启动子上的结合。有趣的是，我们发现 JNK1 酶活性是 Ral 依赖的 ERα 依赖性基因激活所必需的。我们的研究结果表明，Ral 依赖性招募 ERα 到 AP-1 结合位点的作用之一是刺激 JNK1 酶活性。或者，Ral 占据的 ERα 可能在不改变 JNK1 活性的情况下将蛋白底物募集到启动子结合的 JNK1。总的来说，我们的研究揭示了 JNK1 在通过 ERα 确定基因调控结果方面的新作用。
