The orphan nuclear receptor SHP inhibits agonist-dependent transcriptionalactivity of estrogen receptors ER alpha and ER beta

Citation
L. Johansson et al., The orphan nuclear receptor SHP inhibits agonist-dependent transcriptionalactivity of estrogen receptors ER alpha and ER beta, J BIOL CHEM, 274(1), 1999, pp. 345-353
Citations number
61
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
274
Issue
1
Year of publication
1999
Pages
345 - 353
Database
ISI
SICI code
0021-9258(19990101)274:1<345:TONRSI>2.0.ZU;2-1
Abstract
SHP (short heterodimer partner) is an unusual orphan nuclear receptor that contains a putative ligand-binding domain but lacks a conserved DNA-binding domain, Although no conventional receptor function has yet been identified , SHP has been proposed to act as a negative regulator of nuclear receptor signaling pathways, because it interacts with and inhibits DNA binding and transcriptional activity of various nonsteroid receptors, including thyroid hormone and retinoid receptors, We show here that SHP interacts directly w ith agonist-bound estrogen receptors, ER alpha and ER beta, and inhibits ER -mediated transcriptional activation. SHP specifically targets the ligand-r egulated activation domain AF-2 and competes for binding of coactivators su ch as TIF2. Thus, SHP may represent a new category of negative coregulators for ligand-activated nuclear receptors. SHP mRNA is widely expressed in ra t tissues including certain estrogen target tissues, and subcellular locali zation studies demonstrate that SHP is a nuclear protein, suggesting a biol ogical significance of the SHP interactions with ERs. Taken together, these results identify ERs as novel SHP targets and suggest that competition for coactivator-binding is a novel mechanism by which SHP may inhibit nuclear receptor activation.