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

Elizabeth A. Fogarty, Christina K. Matulis, W. Lee Kraus

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)331-338
Number of pages8
JournalMolecular and Cellular Endocrinology
Volume348
Issue number1
DOIs
StatePublished - Jan 2 2012

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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