Phosphorylation of the retinoid x receptor at the omega loop, modulates the expression of retinoic-acid-target genes with a promoter context specificity.
The retinoid response is mediated by two classes of nuclear receptors, the retinoic acid receptors (RARalpha, beta, and gamma) and the retinoid X receptors (RXRalpha, beta, and gamma) which act as ligand-dependent heterodimeric RAR/RXR transcription activators. Like most transcription factors, RARs and RXRs are regulated by phosphorylation processes. Here, we report that stress agents induce RXRalpha phosphorylation, subsequently to the activation of the stress-activated protein kinases cascade (JNKs). This phosphorylation process concerns three residues located in the N-terminal AF-1 domain of RXRalpha and one located in the omega loop of the Ligand Binding Domain. To decipher how stress-induced RXRalpha phosphorylation influences the transcription of RA-target genes, we used a ribotoxic stress agent, anisomycin, which activates signaling kinases without promoting DNA or protein damages, at subinhibitory concentrations. Taking advantage of vectors expressing recombinant RXRalpha mutated at its phosphorylation sites and of F9 cell lines re-expressing the same RXRalpha mutants in an RXRalpha null background, we provide evidence that stress signaling modulates RAR/RXRalpha-mediated transcription, through the phosphorylation of RXRalpha at the residue located in the Omega loop, in a promoter context-dependent manner.
Bruck
Nathalie
N
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM /ULP, BP 10142, 67404 Illkirch Cedex, France.
Bastien
Julie
J
Bour
Gaétan
G
Tarrade
Anne
A
Plassat
Jean-Luc
JL
Bauer
Annie
A
Adam-Stitah
Sylvie
S
Rochette-Egly
Cécile
C
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics; D000072516:Retinoic Acid 4-Hydroxylase; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma; D000099261:Homeobox A1 Protein
D000841:Anisomycin; D003577:Cytochrome P-450 Enzyme System; D018398:Homeodomain Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D018168:Receptors, Retinoic Acid; D000072516:Retinoic Acid 4-Hydroxylase; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D012694:Serine; D014157:Transcription Factors; D014212:Tretinoin; D048051:p38 Mitogen-Activated Protein Kinases; D000097768:Retinoic Acid Receptor gamma; D000099261:Homeobox A1 Protein; C101121:HOXB1 homeodomain protein; C000607072:Rara protein, mouse; C082928:retinoic acid binding protein II, cellular; C082925:retinoic acid receptor beta