Estrogenically regulated LRP16 interacts with estrogen receptor α and enhances the receptor's transcriptional activity

W. D. Han, Y. L. Zhao, Y. G. Meng, L. Zang, Z. Q. Wu, Q. Li, Y. L. Si, K. Huang, J. M. Ba, H. Morinaga, M. Nomura, Y. M. Mu

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Abstract

Previous studies have shown that leukemia related protein 16 (LRP16) is estrogenically regulated and that it can stimulate the proliferation of MCF-7 breast cancer cells, but there are no data on the mechanism of this pathway. Here, we demonstrate that the LRP16 expression is estrogen dependent in several epithelium-derived tumor cells. In addition, the suppression of the endogenous LRP16 in estrogen receptor α (ERα)-positive MCF-7 cells not only inhibits cells growth, but also significantly attenuates the cell line's estrogen-responsive proliferation ability. However, ectopic expression of LRP16 in ERa-negative MDA-MB-231 cells has no effect on proliferation. These data suggest the involvement of LRP16 in estrogen signaling. We also provide novel evidence by both ectopic expression and small interfering RNA knockdown approaches that LRP16 enhances ERα-mediated transcription activity. In stably LRP16-inhibitory MCF-7 cells, the estrogen-induced upregulation of several well-known ERα target genes including cyclin D1 and c-myc is obviously impaired. Results from glutathione S-transferase pull-down and coimmunoprecipitation assays revealed that LRP16 physically interacts with ERα in a manner that is estrogen independent but is enhanced by estrogen. Furthermore, a mammalian two-hybrid assay indicated that the binding region of LRP16 localizes to the A/B activation function 1 domain of ERα. Taken together, these results present new data supporting a role for estrogenically regulated LRP16 as an ERα coactivator, providing a positive feedback regulatory loop for ERα signal transduction.

Original languageEnglish
Pages (from-to)741-753
Number of pages13
JournalEndocrine-Related Cancer
Volume14
Issue number3
DOIs
Publication statusPublished - Sep 1 2007

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All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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