Probing the Functional Link between Androgen Receptor Coactivator and Ligand-binding Sites in Prostate Cancer and Androgen Insensitivity

He, Bin; Gampe, Robert T.; Hnat, Andrew T.; Faggart, Jonathan L.; Minges, John T.; French, Frank S.; Wilson, Elizabeth M.

doi:10.1074/jbc.m511738200

Cited by 66 publications

(60 citation statements)

References 63 publications

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“…M a n u s c r i p t 23 However, in another study the mutant V715M has been reported to display an increased NC-TDI as well as an increased p160 co-activator interaction (He et al, 2006). The mutant H874Y has been studied extensively and this mutant displayed an increased p160 co-activator interaction (Brooke et al, 2008;Duff and McEwan, 2005;He et al, 2006). Contradictory results were reported with respect to the NC-TDI.…”

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 55%

“…The mutation V715M resulted in a small increase of NC-TDI, but in a normal p160 co-activator activation, while for the mutant R726L the reverse was found (Thompson et al, 2001). M a n u s c r i p t 23 However, in another study the mutant V715M has been reported to display an increased NC-TDI as well as an increased p160 co-activator interaction (He et al, 2006). The mutant H874Y has been studied extensively and this mutant displayed an increased p160 co-activator interaction (Brooke et al, 2008;Duff and McEwan, 2005;He et al, 2006).…”

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 87%

“…An affected NC-TDI and TIF2 interaction is also found for two other mutations close to AF2, G743V (PAIS) and V889M (CAIS) (He et al, 2006; A c c e p t e d M a n u s c r i p t 22 Thompson et al, 2001). In close proximity of G743, three mutations are reported in AIS subjects, R871G, S814N and V866M, which were found to have a defective NC-TDI (Ghali et al, 2003).…”

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 97%

“…This mutant displays a decreased NC-TDI, but also an increased androgen equilibrium dissociation constant (Elhaji et al, 2004). For prostate cancer, several mutations (V715M, R726L, H874Y) have been reported displaying either an increased NC-TDI or an increased p160 co-activator activation or both (Thompson et al, 2001;Duff and McEwan, 2005;He et al, 2006;Brooke et al, 2008). The mutation V715M resulted in a small increase of NC-TDI, but in a normal p160 co-activator activation, while for the mutant R726L the reverse was found (Thompson et al, 2001).…”

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 98%

“…In contrast to our study, several studies showed that AR mutations found in subjects with AIS and prostate cancer, can result in an altered NH 2 -/COOH-terminal domain interaction and co-factor interaction. Five mutations resulting in AIS, L712F, F725L, I737T, Q733H and I898T respectively, are located in the hydrophobic region of AF2, which all result in a defective NC-TDI and in a defective interaction with TIF2 (Quigley et al, 2004;He et al, 2006). In addition, the AR mutants F725L and I737T have a defective interaction with SRC1 (Quigley et al, 2004).…”

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 99%

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A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Wong

Hoogerbrugge

Pang

et al. 2008

Molecular and Cellular Endocrinology

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A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH 2 -/COOH-terminal domain interaction and TIF2 co-activation, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abbreviations: aa, amino acid; AD, activation domain; AF2, activation function 2; DHT, 5-dihydrotestosterone; DSD, disorders of sex development; GFP, green fluorescent protein; GSF, genital skin fibroblast; LBD, ligand binding domain; LBP, ligand binding pocket; N-CoR, nuclear receptor co-repressor; NC-TDI, NH 2 -/COOH-terminal domain interaction; NTD, N-terminal transactivation domain; T, testosterone; TIF2, transcriptional intermediary factor 2; wt, wild-type. However, an at least two-fold higher NH 2 -/COOH-terminal domain interaction was found in luciferase and GST pull-down assays. A two-fold increase was also observed for TIF2 (transcription intermediary factor 2) co-activation of the AR F826L COOH-terminal domain. This increase could not be explained by a higher stability of the mutant protein, which was within wild-type range.Repression of transactivation by the nuclear receptor co-repressor (N-CoR) was not affected by the AR F826L mutation. The observed properties of AR F826L would be in agreement with an increased activity rather than with a partial defective AR transcriptional activation. It is concluded that the penoscrotal hypospadias in the present case is caused by an as yet unknown mechanism, which still may involve the mutant AR.

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Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 55%

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 87%

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 97%

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 98%

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 99%

See 3 more Smart Citations

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Wong

Hoogerbrugge

Pang

et al. 2008

Molecular and Cellular Endocrinology

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Modulation of the Androgen Receptor Axis

Mohler

Dalton

2021

Burger's Medicinal Chemistry and Drug Discovery

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The androgen receptor (AR) mediates the endocrine functions of endogenous androgens like testosterone and exerts pleiotropic androgenic (male phenotype development, sexual function) and anabolic (growth and maintenance of musculoskeletal system) effects across most tissues. The AR‐axis, i.e. AR and its downstream effects, is extensively targeted to stimulate anabolism or treat prostatic diseases. Tissue‐selective, direct‐acting synthetic AR agonists are limited in scope by their inadequate separation of anabolic from untoward androgenic or virilizing effects and include FDA approved steroidal androgens (anabolic‐androgenic steroids) and investigational nonsteroidal selective AR modulators (SARMs). Gaining in popularity is testosterone replacement therapy in hypogonadal men. Antagonism of the AR‐axis is common in aging males with androgen‐dependent prostate hyperproliferation [prostate cancer or benign prostatic hyperplasia (BPH)]. Androgen ablation (indirect antagonism) and direct AR antagonism have been the mainstays of prostate cancer therapies for many decades including recent approvals. Indirect antagonists of the AR‐axis include gonadotropin‐releasing hormone agonists or antagonists (androgen‐deprivation therapy), which achieve systemic androgen and estrogen ablation for prostate or breast cancers as a monotherapy or sometimes in combination with steroidogenic enzyme (lyase) inhibitors. DHT‐dependent diseases are treated with 5α‐reductase to block intracrine production of DHT for male pattern baldness and BPH; whereas aromatase inhibitors block androgen metabolism to estrogen in breast cancer. Direct AR antagonists (antiandrogens) with improved potency and anti‐androgenic scope continue to be approved for prostate cancer. Research into innovative ways to directly or indirectly modulate the AR‐axis remains robust, suggesting new therapies will likely be introduced regularly for the foreseeable future.

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Targeting the Nuclear Receptor–Cofactor Interaction

Vaz

Möcklinghoff

Brunsveld

2008

Methods and Principles in Medicinal Chemistry

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The developmental and physiological processes regulated by nuclear receptors are the result of the interplay between the receptors, their small-molecule ligands (hormones), their response elements on the DNA and a large set of interacting proteins, the so-called cofactors [1,2]. Up to recently, the modulation of the function of nuclear receptors concentrated mainly on ligands with agonistic, antagonistic or partial (ant)agonistic properties that bind in the binding pocket of the ligand-binding domain (LBD), also occupied by the natural ligands. These types of ligands have proven very beneficial for the treatment of various diseases and the regulation of hormone functioning, as illustrated by many of the chapters in this book. Some of these ligands have even been shown to feature tissue-specific or -selective (ant) agonistic properties, which is often of crucial importance for the separation of the beneficial effects of nuclear receptor stimulation or inhibition from unwanted sideeffects, regulated by the same receptor [2]. Nevertheless, predictability and control over tissue specificity of these classical ligands is difficult. The physiological effects of some of the nuclear receptor ligands are sometimes also altered over a period of time. A typical example of this is the transition of nuclear receptor ligands used for the treatment of specific cancers from an antagonistic profile into an agonistic profile [3]. Interestingly, there are also nuclear receptors for which, up to now, no ligand, neither of natural nor of synthetic origin, has been found. These so-called orphan receptors seem not to be amenable to modulation by classical ligands.The limitations of the current nuclear receptor ligands generate a continuous quest for new ligands with optimized profiles in both industry and academia. The requirements of the effects of these ligands on the level of the organism are usually quite clear; the translation of these requirements to the level of the conformation of the protein and structure of the ligand is, however, usually not evident. This is due to a major extent to the large plethora of protein-protein interactions between nuclear receptors and their many cofactors [1,2]. Binding of a ligand results in a change of the Nuclear Receptors as Drug Targets. Edited by Eckhard Ottow and Hilmar Weinmann

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Probing the Functional Link between Androgen Receptor Coactivator and Ligand-binding Sites in Prostate Cancer and Androgen Insensitivity

Cited by 66 publications

References 63 publications

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Modulation of the Androgen Receptor Axis

Targeting the Nuclear Receptor–Cofactor Interaction

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