Disrupted Amino- and Carboxyl-Terminal Interactions of the Androgen Receptor Are Linked to Androgen Insensitivity

Thompson, J. S.; Saatcioglu, Fahri; Jänne, Olli A.; Palvimo, Jorma J.

doi:10.1210/mend.15.6.0647

Cited by 94 publications

(31 citation statements)

References 55 publications

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“…Considering that the AR AF-2 is deemed to be the target site for the AR N-terminal WXXLF and FXXLF motifs, which show high affinity binding to the AF-2 domain and is necessary for the N-C interaction (35), suggests potential competition between the three motifs for AR interaction. Indeed, our finding 2 that Tip60 fails to interact with the AR LBD G743V mutant, which has been shown to abolish N-C interaction in the full-length AR context (36), may indicate that Tip60 binds to a site within the LBD that is also required for TD interaction. However, the rapid androgen dissociation kinetics associated with several AR LBD mutants (36) may have distorted our results, such that the failure for a Tip60 interaction may be due to the LBD being in the un-liganded, apo form.…”

Section: Discussionmentioning

confidence: 76%

Tip60 Is a Co-activator Specific for Class I Nuclear Hormone Receptors

Gaughan

Brady

Cook

et al. 2001

Journal of Biological Chemistry

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The nuclear hormone receptor superfamily is composed of a group of hormone-dependent transcription factors that play prominent roles in homeostatic events in vertebrates. A prerequisite for steroid hormone receptor activity is the binding of co-activator molecules to the activation function-2 domain of the receptor. The LXXLL motif/nuclear receptor box, contained within a number of co-activator molecules, mediates the interaction with nuclear hormone receptors. Tip60 (Tat-interactive protein 60 kDa), previously shown to bind to and enhance androgen receptor (AR)-mediated transactivation, contains a single nuclear receptor box at its extreme C terminus. We demonstrate that unlike members of the p160 co-activator family that interact predominantly with the N terminus of the AR in an LXXLL motifindependent manner, the LXXLL motif of Tip60 is required and is sufficient for AR interaction. Furthermore, by using the mammalian two-hybrid system and transient transfection experiments, we show that Tip60 preferentially interacts with and up-regulates class I nuclear receptors, suggesting that Tip60 is a steroid hormone receptor-specific co-activator. We conclude that Tip60 may specifically regulate a subset of nuclear hormone receptors, giving an indication to how regulated nuclear receptor activation can be achieved.The androgen receptor (AR), 1 a member of the steroid hormone receptor family, is a ligand-inducible transcription factor that plays a key role in the growth, development, and transformation of the prostate gland (1, 2). The AR, in common with other members of the nuclear hormone receptor (NR) family, is a modular protein containing distinct functional domains (for review, see Ref.3). DNA interaction involves the centrally positioned double zinc finger-containing DNA-binding domain (DBD) (4, 5), which is highly conserved throughout the family of nuclear receptors (NR). Hormone binding is performed by the C-terminal ligand-binding domain (LBD), a structurally conserved region within the family of NRs, containing 12 ␣-helices (H1-H12) (6 -8), which in addition mediates homodimerization and plays a role in transcriptional activation. This latter function is performed by the extreme C-terminal helix H12 of the LBD, termed activation function-2 (AF-2) (9), a ligand-dependent transcriptional activator which, in combination with the N-terminal transactivation domain (TD), is able to activate receptor-mediated gene expression. Although not fully defined, the AF-2 domain of NRs has been proposed to mediate direct interactions with a number of co-activator proteins necessary for the full transcriptional activity of the receptor (8, 10). To date, numerous co-activator molecules have been characterized, such as members of the p160 family, including SRC-1 (steroid receptor co-activator-1) (11) and GRIP-1 (glucocorticoid receptor-interacting protein-1) (12); the CREB-binding protein (CBP)/p300 proteins (13, 14) and p300/CBP-associating factor (15). The finding that many of these co-activator molecules are histone acetyltr...

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Section: Discussionmentioning

confidence: 76%

Tip60 Is a Co-activator Specific for Class I Nuclear Hormone Receptors

Gaughan

Brady

Cook

et al. 2001

Journal of Biological Chemistry

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“…We measured the strength of the interaction between each compound and the receptor in competitive binding studies, whereas the ability of the ligand to confer the appropriate conformation for cofactor recruitment was measured in the TRAF2 GRIP-1 assay. The N-terminal domain of AR contains a ligand-independent activator function (AF-1) but also functions largely as ligand-dependent cofactor for the LBD, a function that we postulated, based on human genetic data, functions in reproductive physiology (25)(26)(27)38). This receptor function was monitored in the VIRCON mammalian two-hybrid assay.…”

Section: Discussionmentioning

confidence: 99%

“…AR is maximally active when the ligand promotes an interaction between the N-and C-terminal AR domains (the N/C interaction). Interestingly, mutations in the N-or C-terminal domain of AR that impair this interaction were found in incompletely virilized patients with partial androgen insensitivity; some of these mutations also inhibit the recruitment of transcriptional cofactors to AF-2 (25)(26)(27). These genetic data suggest that synthetic ligands that promote the transactivation activity of AR while exhibiting reduced ability to support the N/C interaction or cofactor recruitment could provide tissue selectivity in vivo.…”

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confidence: 99%

Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Schmidt

Kimmel

Bai

et al. 2010

Journal of Biological Chemistry

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Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40 -80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

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“…Transactivation functions reside mainly in the ARTAD, and very minimal activity can be demonstrated in the ARLBD (2,3). Unlike other steroid receptors, transactivity depends on ligand-induced interactions between the ARTAD and ARLBD, and mutations that reduce TAD-LBD interactions affect AR activity, causing androgen insensitivity syndromes (4)(5)(6). Like other transcription regulators, the promoter-bound AR serves as a nidus to recruit cofactors that up-regulate (coactivators) or down-regulate (corepressors) AR activity.…”

mentioning

confidence: 99%

Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions

Loy

Sim²,

Yong³

2003

Proc. Natl. Acad. Sci. U.S.A.

180

203

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The androgen receptor (AR), a nuclear transcription factor, mediates male sexual differentiation, and its excessive action is associated with prostate cancer. We have characterized a negative regulatory domain in the AR hinge region, which interacted with filamin A (FLNa), an actin-binding cytoskeletal protein. FLNa interfered with AR interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. Although full-length FLNa was predominantly cytoplasmic, a C-terminal 100-kDa fragment of FLNa colocalized with AR to the nucleus. This naturally occurring FLNa fragment repressed AR transactivation and disrupted AR interdomain interactions and transcriptional intermediary factor 2-activated AR function in a manner reminiscent of full-length FLNa, raising the possibility that the inhibitory effects of cytoplasmic FLNa may be transduced through this fragment, which can localize to the nucleus and form part of the pre-initiation complex. This unanticipated role of FLNa adds to the growing evidence for the involvement of cytoskeletal proteins in transcription regulation. T he androgen receptor (AR), a member of the steroid͞ nuclear receptor superfamily, mediates male morphogenesis in utero, gametogenesis and prostate growth at puberty, and the development of prostatic cancer in older men. The AR has four principal domains: a large N-terminal transactivation domain (ARTAD), a DNA-binding domain (ARDBD), and a hinge domain, followed by the C-terminal ligand-binding domain (ARLBD). In the absence of androgen, it is generally accepted that AR is cytoplasmic. Androgens bind specifically to a ligandbinding pocket in the lower half of the LBD, causing a conformation change (1), the release of heat-shock proteins, and translocation of the ligand-AR complex to the nucleus, where the DBD interacts with specific response elements on the promoters of target genes. Transactivation functions reside mainly in the ARTAD, and very minimal activity can be demonstrated in the ARLBD (2, 3). Unlike other steroid receptors, transactivity depends on ligand-induced interactions between the ARTAD and ARLBD, and mutations that reduce TAD-LBD interactions affect AR activity, causing androgen insensitivity syndromes (4-6). Like other transcription regulators, the promoter-bound AR serves as a nidus to recruit cofactors that up-regulate (coactivators) or down-regulate (corepressors) AR activity. The most clearly defined class of coactivators is the p160͞steroid receptor coactivator (SRC) family. They include SRC1, transcriptional intermediary factor 2 (SRC2͞TIF2), and SRC3͞TRAM1͞A IB1͞pCIP͞ACTR͞ RAC3, who bind hydrophobic grooves in the LBDs of steroid receptors via LXXLL motifs in their nuclear-receptorinteracting boxes, draw in cAMP-response element-binding protein (CBP͞p300), pCAF, and other cofactors to modulate chromatin and initiate transcription by RNA polymerase II (7). Of the p160͞SRC proteins, TIF2 interacts most strongly with the AR (8) and, in concert with CBP͞p30...

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Disrupted Amino- and Carboxyl-Terminal Interactions of the Androgen Receptor Are Linked to Androgen Insensitivity

Cited by 94 publications

References 55 publications

Tip60 Is a Co-activator Specific for Class I Nuclear Hormone Receptors

Tip60 Is a Co-activator Specific for Class I Nuclear Hormone Receptors

Discovery of the Selective Androgen Receptor Modulator MK-0773 Using a Rational Development Strategy Based on Differential Transcriptional Requirements for Androgenic Anabolism Versus Reproductive Physiology

Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions

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