Journal
EMBO JOURNAL
Volume 30, Issue 3, Pages 468-479Publisher
WILEY
DOI: 10.1038/emboj.2010.337
Keywords
androgen receptor; E3 ligases; phosphorylation; proteasome; TFIIH
Categories
Funding
- European Research Council
- French National Research Agency [ANR-05-PCOD-032-03, ANR-06-BLAN-0141-01, ANR-08-MIEN-02203, ANR-08GENOPAT042]
- Association pour la Recherche sur le Cancer [3153]
- Fondation pour la Recherche Medicale
- CDD INSERM
- Agence Nationale de la Recherche (ANR) [ANR-06-BLAN-0141] Funding Source: Agence Nationale de la Recherche (ANR)
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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 over-expressing 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. The EMBO Journal (2011) 30, 468-479. doi:10.1038/emboj.2010.337; Published online 14 December 2010
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