Activation of estrogen receptor alpha by raloxifene through an activating protein-1-dependent tethering mechanism in human cervical epithelial cancer cells: A role for c-Jun N-terminal kinase

作者：Fogarty Elizabeth A; Matulis Christina K; Kraus W Lee^*

来源：Molecular and Cellular Endocrinology, 2012, 348(1): 331-338.

DOI：10.1016/j.mce.2011.09.032

• Raloxifene
• Activating protein-1 (AP-1)
• c-Fos
• c-Jun N-terminal kinase (JNK1)
• Estrogen receptor
• Transcriptional activation

Nuclear estrogen receptor alpha (ER alpha) 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 ER alpha 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 ER alpha at the promoter in a c-Fos-dependent manner. Interestingly, we found that JNK1 enzymatic activity is required for Ral-dependent gene activation through ER alpha. Our results suggest that one role for Rat-dependent recruitment of ER alpha to the AP-1 binding site is to stimulate JNK1 enzymatic activity. Alternatively, Ral-occupied ER alpha 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 ER alpha. C) 2011 Elsevier Ireland Ltd.

• 出版日期2012-1-2