title: The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process.
abstract: In response to hormonal stimuli, a cascade of hierarchical post-translational modifications of nuclear receptors are required for the correct expression of target genes. Here, we show that the transcription factor TFIIH, via its cdk7 kinase, phosphorylates the androgen receptor (AR) at position AR/S515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the MDM2 E3 ligase, the subsequent ubiquitination of AR at the promoter of target genes and its degradation by the proteasome machinery. Impaired phosphorylation disrupts the transactivation, as observed in cells either overexpressing the non-phosphorylated AR/S515A, isolated from xeroderma pigmentosum patient (bearing a mutation in XPD subunit of TFIIH), or in which cdk7 kinase was silenced. Indeed, besides affecting the cyclic recruitment of the transcription machinery, the AR phosphorylation defect favourizes to the recruitment of the E3 ligase CHIP instead of MDM2, at the PSA promoter, that will further attract the proteasome machinery. These observations illustrate how the TFIIH phosphorylation might participate to the transactivation by regulating the nuclear receptors turnover.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université de Strasbourg, Illkirch cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chymkowitch
authors.forename: Nicolas
authors.initials: N
authors.lastname: Le May
authors.forename: Pierre
authors.initials: P
authors.lastname: Charneau
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Compe
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D047369:Chromatin Immunoprecipitation; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D051758:Transcription Factor TFIIH / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014983:Xeroderma Pigmentosum / Q000235:genetics
chemical_list: D011944:Receptors, Androgen; D051758:Transcription Factor TFIIH; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex