Regulation of estrogen receptor α N-terminus conformation and function by peptidyl prolyl isomerase Pin1

Mol Cell Biol. 2012 Jan;32(2):445-57. doi: 10.1128/MCB.06073-11. Epub 2011 Nov 7.

Abstract

Estrogen receptor alpha (ERα), a key driver of growth in the majority of breast cancers, contains an unstructured transactivation domain (AF1) in its N terminus that is a convergence point for growth factor and hormonal activation. This domain is controlled by phosphorylation, but how phosphorylation impacts AF1 structure and function is unclear. We found that serine 118 (S118) phosphorylation of the ERα AF1 region in response to estrogen (agonist), tamoxifen (antagonist), and growth factors results in recruitment of the peptidyl prolyl cis/trans isomerase Pin1. Phosphorylation of S118 is critical for Pin1 binding, and mutation of S118 to alanine prevents this association. Importantly, Pin1 isomerizes the serine118-proline119 bond from a cis to trans isomer, with a concomitant increase in AF1 transcriptional activity. Pin1 overexpression promotes ligand-independent and tamoxifen-inducible activity of ERα and growth of tamoxifen-resistant breast cancer cells. Pin1 expression correlates with proliferation in ERα-positive rat mammary tumors. These results establish phosphorylation-coupled proline isomerization as a mechanism modulating AF1 functional activity and provide insight into the role of a conformational switch in the functional regulation of the intrinsically disordered transactivation domain of ERα.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Estrogen Receptor alpha / chemistry*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Tamoxifen / pharmacology
  • Transcriptional Activation

Substances

  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Tamoxifen
  • PIN1 protein, human
  • Peptidylprolyl Isomerase