title: Cyclin H binding to the RARalpha activation function (AF)-2 domain directs phosphorylation of the AF-1 domain by cyclin-dependent kinase 7.
abstract: The transcriptional activity of nuclear retinoic acid receptors (RARs), which act as RAR/retinoid X receptor (RXR) heterodimers, depends on two activation functions, AF-1 and AF-2, which are targets for phosphorylations and synergize for the activation of retinoic acid target genes. The N-terminal AF-1 domain of RARalpha is phosphorylated at S77 by the cyclin-dependent kinase (cdk)-activating kinase (CAK) subcomplex (cdk7/cyclin H/MAT1) of the general transcription factor TFIIH. Here, we show that phosphorylation of S77 governing the transcriptional activity of RARalpha depends on cyclin H binding at a RARalpha region that encompasses loop 8-9 and the N-terminal tip of helix 9 of the AF-2 domain. We propose a model in which the structural constraints of this region control the architecture of the RAR/RXR/TFIIH complex and therefore the efficiency of RARalpha phosphorylation by cdk7. To our knowledge, this study provides the first example of a cooperation between the AF-2 and AF-1 domains of RARs through a kinase complex.
authors.affiliation: Département de Biologie Cellulaire et de Transduction du Signal, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, UMR 7104, Illkirch, France.
authors.forename: Gaétan
authors.initials: G
authors.lastname: Bour
authors.forename: Emilie
authors.initials: E
authors.lastname: Gaillard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bruck
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lalevée
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Plassat
authors.forename: Didier
authors.initials: D
authors.lastname: Busso
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Samama
authors.forename: Cécile
authors.initials: C
authors.lastname: Rochette-Egly
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D056748:Cyclin H; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D017931:DNA Primers; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018411:Spodoptera; D014158:Transcription, Genetic / Q000502:physiology; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D056748:Cyclin H; D016213:Cyclins; D017931:DNA Primers; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase