Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

Abstract

2The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide new molecular insights into the regulation of androgen receptor function and suggest new strategies for treating prostate cancer.3 Highlights -A short motif in transactivation unit 5 recruits the transcription machinery to the AR -The motif is intrinsically disordered but folds into a helix upon binding -Phosphorylation of Ser 424 enhances the interaction and is essential for transcription -The interaction is a potential therapeutic target for castration-resistant prostate cancer 4 Graphical abstract 5 IntroductionThe activation of transcription relies on interactions between specific transcription factors and general transcription regulators that can mediated by transcriptional co-activators (Fuda et al., 2009). It is important to characterize these interactions because their inhibition by small molecules or other biological tools offers opportunities for therapeutic intervention in many disease areas, including oncology (Darnell, 2002). Since they involve intrinsically disordered transactivation domains the associated complexes are however transient, marginally stable and challenging to study (Wright and Dyson, 2015).One case where inhibiting these interactions is appealing is castration resistant prostate cancer (CRPC). This condition is suffered by prostate cancer patients that are refractory to hormone therapy, which is based on preventing the activation of the androgen receptor (AR). The mechanisms that allow cell proliferation under these conditions are not yet fully characterized but it is becoming clear that they include expression of constitutively active AR isoforms lacking the ligand binding domain (Miyamoto et al., 2015;Robinson et al., 2015).The complexes formed by the transactivation domain of AR (Lavery and McEwan, 2008a) and general transcription regulators are targets to interfere with CRPC (Sadar, 2011) because inhibiting their formation can lead to a decrease in AR transcriptional activity and in the proliferation of prostate cancer cells. Here we report the structural basis for the interaction of the transactivation domain of AR and the C-terminal domain of subunit 1 of the general transcription regulator TFIIF (RAP74-CTD), which involves the partial folding upon binding of a ca 10-residue motif in this receptor and contributes to the initiation of transcription (Choudhry et al., 2006;McEwan and Gustafsson, 1...

Dissecting the transactivation domain (tAD) of the transcription factor c‐Myb to assess recent models of tAD function

“…This SLM therefore appears to be involved in a repressive function, as previously reported [53]. The WHSTT motif does not seem to be very important for the activity of c-Myb (P = 0.038) and therefore is probably not playing the same role as reported for androgen receptor [55].…”

Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in the activation domain of a transcription factor

“…Our results provide a plausible rationale as they suggest that variations in the length of polyQ tracts result in changes in the secondary structure of the transactivation domain of transcription factors. Indeed, such variations can affect the strength of the proteinprotein interactions 52 , particularly of those regulating transcription 53 , which include interactions with transcriptional coregulators and with general transcription factors. Whether a certain change in tract length causes a decrease or an increase in activity might depend on whether the polyQ tract and its flanking regions are involved in interactions with transcriptional coactivators or corepressors and should therefore be contextdependent, as found experimentally 51,54 .…”

Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on

“…Once bound to the chromatin, AR recruits numerous coregulatory proteins to modulate transcription, leading to cell growth and survival responses [ 17 , 18 , 19 ]. At the genome level, the AR recruits members of the basal transcription machinery, for instance TATA-box-binding protein (TBP) and transcription factor IIF (TFIIF), and also other pivotal coregulators such as different members of the p160 family of coactivators and cAMP-response element-binding protein (CREB)-binding protein (CBP) (see [ 18 , 20 , 21 , 22 ]). However, this “simple” monomer–dimer equilibrium transition model is being challenged by ongoing research, and important questions remain regarding the possible additional role of chaperone proteins [ 23 , 24 , 25 , 26 ], the cellular location of dimerization [ 15 , 27 , 28 ] and the influence of response element architecture on receptor activity.…”