Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif - Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 c
[en] Estrogen receptor alpha (ERalpha) belongs to the superfamily of nuclear receptors and as such acts as a ligand-modulated transcription factor. Ligands elicit in ERalpha conformational changes leading to the recruitment of coactivators required for the transactivation of target genes via cognate response elements. In many cells, activated ERalpha also undergoes downregulation by proteolysis mediated by the ubiquitin/proteasome system. Although these various molecular processes have been well characterized, little is known as to which extent they are interrelated. In the present study, we used a panel of type I (estradiol derivatives and 'linear', non-steroidal ligands) and type II ('angular' ligands) estrogens, in order to identify possible relationships between ligand binding affinity, recruitment of LxxLL-containing coactivators, ERalpha downregulation in MCF-7 cells and related transactivation activity of ligand-bound ERalpha. For type I estrogens, there was a clear-cut relationship between ligand binding affinity, hydrophobicity around C-11 of estradiol and ability of ERalpha to associate with LxxLL motifs, both in cell-free condition and in vivo (MCF-7 cells). Moreover, LxxLL motif recruitment by ERalpha seemed to be a prerequisite for the downregulation of the receptor. By contrast, type II ligands, as well as estradiol derivatives bearing a bulky side chain at 11beta, had much less tendency to promote ERalpha-LxxLL interaction or even behaved as antagonists in this respect, in agreement with the well known partial estrogenicity/antiestrogenicity of some of these compounds. Interestingly, some type II ligands which antagonized LxxLL motif recruitment were nonetheless able to enhance ERalpha-mediated gene transactivation.
Disciplines :
Immunology & infectious disease Oncology
Author, co-author :
Bourgoin-Voillard, Sandrine
Gallo, Dominique
Laïos, Ioanna
Cleeren, Anny
El Bali, Latifa
Jacquot, Yves
Nonclercq, Denis ; Université de Mons > Faculté de Médecine et de Pharmacie > Service d'Histologie
Laurent, Guy ; Université de Mons > Faculté de Médecine et de Pharmacie > Histologie
Tabet, Jean-Claude
Leclercq, Guy
Language :
English
Title :
Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif - Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 c
Publication date :
01 March 2010
Journal title :
Biochemical Pharmacology
ISSN :
0006-2952
Publisher :
Elsevier, Netherlands
Volume :
79
Issue :
5
Pages :
746-757
Peer reviewed :
Peer Reviewed verified by ORBi
Research unit :
M118 - Histologie
Research institute :
R550 - Institut des Sciences et Technologies de la Santé
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