Nucleic Acids Research, 2003, Vol. 31, No. 18 5266-5274
© 2003 Oxford University Press
Ligand-independent activation of estrogen receptor 
by XBP-1
1 Beijing Institute of Biotechnology, Beijing 100850, Peoples Republic of China, 2 Fujian Science and Technology University, Fuzhou 350002, Peoples Republic of China and 3 Beijing Institute of Radiation Medicine, Beijing 100850, Peoples Republic of China
*To whom correspondence should be addressed at Beijing Institute of Biotechnology, 27 Tai-Ping Lu Rd, Beijing 100850, Peoples Republic of China. Tel: +86 10 6818 0809; Fax: +86 10 6824 8045; Email: yeqn{at}nic.bmi.ac.cn
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 ER
status in breast tumors. However, the role of XBP-1 in ER 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 ER-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 ER transactivation were observed when they were co-expressed with full-length ER. SRC-1, the p160 steroid receptor coactivator family member, synergized with XBP-1S or XBP-1U to potentiate ER activity. XBP-1S and XBP-1U bound to the ER both in vitro and in vivo in a ligand-independent fashion. XBP-1S and XBP-1U interacted with the ER region containing the DNA-binding domain. The ER-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 ER transactivation by XBP-1S and XBP-1U. These findings suggest that XBP-1S and XBP-1U may directly modulate ER 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.
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