A SNP in Steroid Receptor Coactivator-1 Disrupts a GSK3β Phosphorylation Site and Is Associated with Altered Tamoxifen Response in Bone
dc.contributor.author | Hartmaier, R.J. | |
dc.contributor.author | Richter, A.S. | |
dc.contributor.author | Gillihan, R.M. | |
dc.contributor.author | Sallit, J.Z. | |
dc.contributor.author | McGuire, S.E. | |
dc.contributor.author | Wang, J. | |
dc.contributor.author | Lee, A.V. | |
dc.contributor.author | Osborne, C.K. | |
dc.contributor.author | O'Malley, B.W. | |
dc.contributor.author | Brown, P.H. | |
dc.contributor.author | Xu, J. | |
dc.contributor.author | Skaar, Todd C. | |
dc.contributor.author | Philips, S. | |
dc.contributor.author | Rae, J.M. | |
dc.contributor.author | Azzouz, F. | |
dc.contributor.author | Li, L. | |
dc.contributor.author | Hayden, J. | |
dc.contributor.author | Henry, N.L. | |
dc.contributor.author | Nguyen, A.T. | |
dc.contributor.author | Stearns, V. | |
dc.contributor.author | Hayes, D.F. | |
dc.contributor.author | Flockhart, D.A. | |
dc.contributor.author | Oesterreich, S. | |
dc.date.accessioned | 2022-10-10T20:01:32Z | |
dc.date.available | 2022-10-10T20:01:32Z | |
dc.date.issued | 2012-02 | |
dc.description.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 GSK3β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3β-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 GSK3β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women. | en_US |
dc.identifier.citation | Hartmaier RJ, Richter AS, Gillihan RM, et al. A SNP in steroid receptor coactivator-1 disrupts a GSK3β phosphorylation site and is associated with altered tamoxifen response in bone. Mol Endocrinol. 2012;26(2):220-227. doi:10.1210/me.2011-1032 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/30312 | |
dc.language.iso | en_US | en_US |
dc.publisher | Oxford University Press | en_US |
dc.relation.isversionof | 10.1210/me.2011-1032 | en_US |
dc.subject | Hormonal antineoplastic agents | en_US |
dc.subject | Pathologic bone demineralization | en_US |
dc.subject | Estrogen receptors | en_US |
dc.subject | Tamoxifen | en_US |
dc.title | A SNP in Steroid Receptor Coactivator-1 Disrupts a GSK3β Phosphorylation Site and Is Associated with Altered Tamoxifen Response in Bone | en_US |
dc.type | Article | en_US |
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