A snp in steroid receptor coactivator-1 disrupts a gsk3β phosphorylation site and is associated with altered tamoxifen response in bone

R. J. Hartmaier, A. S. Richter, R. M. Gillihan, J. Z. Sallit, S. E. Mcguire, J. Wang, A. V. Lee, C. K. Osborne, B. W. O'Malley, P. H. Brown, J. Xu, T. C. Skaar, S. Philips, J. M. Rae, F. Azzouz, L. Li, J. Hayden, N. L. Henry, A. T. Nguyen, V. StearnsD. F. Hayes, D. A. Flockhart, S. Oesterreich

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3) β phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3 β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3 β -mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3 β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.

Original languageEnglish (US)
Pages (from-to)220-227
Number of pages8
JournalMolecular Endocrinology
Volume26
Issue number2
DOIs
StatePublished - Jan 1 2012

Keywords

  • Ligands: tamoxifen17β-Estradiol
  • Nursa molecule pages†: coregulators: src-1

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Hartmaier, R. J., Richter, A. S., Gillihan, R. M., Sallit, J. Z., Mcguire, S. E., Wang, J., Lee, A. V., Osborne, C. K., O'Malley, B. W., Brown, P. H., Xu, J., Skaar, T. C., Philips, S., Rae, J. M., Azzouz, F., Li, L., Hayden, J., Henry, N. L., Nguyen, A. T., ... Oesterreich, S. (2012). A snp in steroid receptor coactivator-1 disrupts a gsk3β phosphorylation site and is associated with altered tamoxifen response in bone. Molecular Endocrinology, 26(2), 220-227. https://doi.org/10.1210/me.2011-1032