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Ligand-independent activation of estrogen receptor alpha by XBP-1.

The estrogen receptor (ER) is a member of a large superfamily of nuclear receptors that regulates the transcription of estrogen-responsive genes. Several recent studies have demonstrated that XBP-1 mRNA expression is associated with ERalpha status in breast tumors. However, the role of XBP-1 in ERalpha signaling remains to be elucidated. More recently, two forms of XBP-1 were identified due to its unconventional splicing. We refer to the spliced and unspliced forms of XBP-1 as XBP-1S and XBP-1U, respectively. Here, we report that XBP-1S and XBP-1U enhanced ERalpha-dependent transcriptional activity in a ligand-independent manner. XBP-1S had stronger activity than XBP-1U. The maximal effects of XBP-1S and XBP-1U on ERalpha transactivation were observed when they were co-expressed with full-length ERalpha. SRC-1, the p160 steroid receptor coactivator family member, synergized with XBP-1S or XBP-1U to potentiate ERalpha activity. XBP-1S and XBP-1U bound to the ERalpha both in vitro and in vivo in a ligand-independent fashion. XBP-1S and XBP-1U interacted with the ERalpha region containing the DNA-binding domain. The ERalpha-interacting regions on XBP-1S and XBP-1U have been mapped to two regions, including the N-terminal basic region leucine zipper domain (bZIP) and the C-terminal activation domain. The bZIP-deleted mutants of XBP-1S and XBP-1U completely abolished ERalpha transactivation by XBP-1S and XBP-1U. These findings suggest that XBP-1S and XBP-1U may directly modulate ERalpha signaling in both the absence and presence of estrogen and, therefore, may play important roles in the proliferation of normal and malignant estrogen-regulated tissues.

Pubmed ID: 12954762

Authors

  • Ding L
  • Yan J
  • Zhu J
  • Zhong H
  • Lu Q
  • Wang Z
  • Huang C
  • Ye Q

Journal

Nucleic acids research

Publication Data

September 15, 2003

Associated Grants

None

Mesh Terms

  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • DNA-Binding Proteins
  • Electrophoretic Mobility Shift Assay
  • Estrogen Receptor alpha
  • Estrogens
  • Histone Acetyltransferases
  • Humans
  • Ligands
  • Luciferases
  • Nuclear Receptor Coactivator 1
  • Protein Binding
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Response Elements
  • Transcription Factors
  • Transcription, Genetic
  • Transfection