PIAS4 represses vitamin D receptor-mediated signaling and acts as an E3-SUMO ligase towards vitamin D receptor

J Steroid Biochem Mol Biol. 2012 Oct;132(1-2):24-31. doi: 10.1016/j.jsbmb.2012.04.006. Epub 2012 Apr 27.

Abstract

The present study investigated the potential for members of the protein inhibitors of activated STAT (PIAS) family to function as co-regulators of the vitamin D signal pathway. Among the PIAS proteins evaluated, we establish PIAS4 as a potent inhibitor of the transcriptional responses of the CYP3A4 and CYP24A1 target genes to the active hormonal form of vitamin D, a repression that was observed to be dependent upon an intact SUMO-ligase function of PIAS4. We report that PIAS4 represents a direct binding partner for vitamin D receptor (VDR) and also facilitates its modification with SUMO2, a process that preferentially occurs on the apo-form of VDR and which is reversed upon binding of ligand. Our results implicate PIAS4 and the process of SUMOylation as important modulators of VDR-mediated signaling which may both represent flexible mechanistic components as to how vitamin D achieves its pleiotropic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochrome P-450 CYP3A / genetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT / metabolism*
  • Receptors, Calcitriol / metabolism*
  • Signal Transduction
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Steroid Hydroxylases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Vitamin D3 24-Hydroxylase

Substances

  • PIAS4 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT
  • Receptors, Calcitriol
  • SUMO2 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Steroid Hydroxylases
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase
  • Ubiquitin-Protein Ligases