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A SNP in steroid receptor coactivator-1 disrupts a GSK3β phosphorylation site and is associated with altered

R J Hartmaier1, A S Richter, R M Gillihan

  • 1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Molecular Endocrinology (Baltimore, Md.)
|December 17, 2011
PubMed

Insights

A single nucleotide polymorphism (SNP) in steroid receptor coactivator-1 (SRC-1) impairs estrogen receptor (ER) coactivation. This SRC-1 variant is linked to reduced bone mineral density in women treated with tamoxifen.

Area of Science:

  • Endocrinology
  • Genetics
  • Bone Biology

Background:

  • Steroid receptor coactivator (SRC)-1 enhances estrogen receptor (ER) transcriptional activity, crucial for bone health.
  • SRC-1 influences responses to estrogen and selective ER modulators (SERMs) like tamoxifen.
  • Genetic variations, such as single nucleotide polymorphisms (SNPs), may alter SRC-1 function and clinical outcomes.

Purpose of the Study:

  • To investigate the functional impact of the nonsynonymous SRC-1 SNP (rs1804645; P1272S) on ER coactivation by estrogen and tamoxifen.
  • To explore the molecular mechanisms underlying the altered function of the SRC-1 P1272S variant.
  • To assess the association between the SRC-1 P1272S variant and bone mineral density response to tamoxifen treatment.

Main Methods:

  • In vitro coactivation assays using cell lines to compare wild-type SRC-1 and SRC-1 P1272S.
  • Protein half-life studies and in vitro kinase assays to investigate phosphorylation at the P1272S site.
  • Analysis of glycogen synthase kinase 3 beta (GSK3β) knockdown effects on SRC-1 protein levels.
  • Clinical association study examining SRC-1 P1272S genotype and bone mineral density in women receiving tamoxifen.

Main Results:

  • SRC-1 P1272S exhibited reduced coactivation of ER compared to wild-type SRC-1.
  • The P1272S substitution disrupts a critical GSK3β phosphorylation site, leading to altered protein stability.
  • Knockdown of GSK3β mimicked the effect of the P1272S variant on SRC-1 protein levels.
  • The SRC-1 P1272S variant was associated with decreased hip and lumbar bone mineral density in women undergoing tamoxifen therapy.

Conclusions:

  • The identified functional genetic variant, SRC-1 P1272S, demonstrates decreased coactivator activity due to impaired GSK3β phosphorylation.
  • This genetic variation may contribute to reduced bone mineral density in women treated with tamoxifen.
  • Findings highlight the clinical relevance of SRC-1 genetic variants in modulating SERM efficacy for bone health.

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