A5056247791- Prostate Cancer Treatment and Research
- Estrogen and related hormone effects
- Hormonal and reproductive studies
- Sexual Differentiation and Disorders
- Mass Spectrometry Techniques and Applications
- Cancer, Lipids, and Metabolism
- Hormonal Regulation and Hypertension
- Ubiquitin and proteasome pathways
- Receptor Mechanisms and Signaling
- Genomics and Chromatin Dynamics
- Radiopharmaceutical Chemistry and Applications
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- DNA and Nucleic Acid Chemistry
- Retinoids in leukemia and cellular processes
- Advanced Proteomics Techniques and Applications
- Steroid Chemistry and Biochemistry
- Genetic Neurodegenerative Diseases
- Epoxy Resin Curing Processes
- Cancer-related gene regulation
- Synthesis and properties of polymers
- Nuclear Receptors and Signaling
- RNA Research and Splicing
- Protein Degradation and Inhibitors
- ATP Synthase and ATPases Research
- Cytokine Signaling Pathways and Interactions
University of Aberdeen
2015-2025
Institute of Medical Sciences
2000-2018
Forest Research
2016
Christie's
2016
Institute of Cancer Research
2012-2015
Addenbrooke's Hospital
2015
Prostate Cancer UK
2015
Cancer Research UK
2015
Freemasons Foundation Centre for Men's Health
2015
University of Cambridge
2014-2015
Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and disease progresses to lethal castration-resistant (CRPC). The mechanisms that drive CRPC are incompletely understood, may involve constitutively active AR splice variants lack LBD. N-terminal (NTD) is essential activity, targeting this with small-molecule inhibitors complicated by its intrinsic disorder. Here we investigated EPI-001, a antagonist of NTD...
Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment castration and/or an antiandrogen. Abiraterone, a rationally designed inhibitor of CYP17A1 recently approved for the docetaxel-treated castration-resistant prostate (CRPC), is often effective, but requires coadministration glucocorticoids to curtail side effects. Here, we hypothesized that progressive disease on abiraterone may occur secondary glucocorticoid-induced activation...
Castration-resistant prostate cancer is the lethal condition suffered by patients that become refractory to androgen deprivation therapy. EPI-001 a recently identified compound active against this modulates activity of receptor, nuclear receptor essential for disease progression. The mechanism which exerts its inhibitory however not yet fully understood. Here we show, using high resolution solution magnetic resonance spectroscopy, selectively interacts with partially folded region...
Persistent androgen receptor (AR) transcriptional activity is clinically evident in castration-resistant prostate cancer (CRPC). Therefore, AR remains as a viable therapeutic target for CRPC. All current hormonal therapies the C-terminus ligand-binding domain (LBD) of AR. By using EPI to activation function-1 (AF-1), N-terminal that essential transactivation, we evaluate ability overcome several relevant AR-related mechanisms resistance.To study effect on against overexpressed coactivators,...
The human androgen receptor (AR) is a ligand-activated transcription factor that regulates genes important for male sexual differentiation and development. To better understand the role of as we have studied mechanism action N-terminal transactivation function. In protein–protein interaction assay AR N terminus (amino acids 142–485) selectively bound to basal factors TFIIF TATA-box-binding protein (TBP). Reconstitution activity in vitro revealed 142–485 fused LexA DNA-binding domain was...
A 58-amino acid polypeptide containing the functional core region, tau 1 core, of major transactivation domain human glucocorticoid receptor has been expressed in Escherichia coli and purified to homogeneity. The retains 60-70% activity intact when assayed vivo or vitro. This report describes a structural characterization peptide fragment. Circular dichroism spectroscopy shows that larger fragment encompassing are largely unstructured water solution under variety pH conditions. however,...
The androgen receptor (AR) is a member of the nuclear superfamily. Sequences within large amino-terminal domain have been shown to be important for transactivation and protein-protein interactions; however, little known about structure folding this region. In present study we show that 344-amino acid polypeptide representing main determinants has propensity form α-helical mutations which disrupt putative helical regions alter conformation. Folding AR was observed in presence...
The androgen receptor (AR) is a member of the nuclear hormone family transcription factors that plays critical role in regulating expression genes involved prostate development and transformation. Upon binding, AR associates with numerous co-regulator proteins regulate activation status target via flux to post-translational modification histones receptor. Here we show interacts directly methylated by histone methyltransferase enzyme SET9. Methylation on lysine 632 necessary for enhancing...
Androgen receptor (AR) mediates the growth of prostate cancer throughout its course development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded proteasomes after ligand binding. Thus, targeting requires development agents that can sustainably degrade variant isoforms for effective therapy. Here we report discovery...
Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs treat castration- and drug-resistant cancers.Second-generation AR pan antagonist UT-34 was selected from a library of compounds tested in binding transactivation assays. using biophysical methods for the activation function-1 (AF-1)...
c-Myc is a member of family sequence specific-DNA binding proteins that are thought to regulate the transcription genes involved in normal cell growth, differentiation, and apoptosis. In order understand how human c-myc functions as factor, we have studied mechanism action structure N-terminal transactivation domain, amino acids 1-143. protein interaction assay, c-myc1-143 bound selectively two basal factors, TATA (TBP) RAP74 subunit TFIIF. Furthermore, isolated domain competed for limiting...
The aryl hydrocarbon (or dioxin) receptor (AhR) is a ligand-activated basic helix-loop-helix (bHLH) protein that heterodimerizes with the bHLH AhR nuclear translocator (ARNT) to form complex binds xenobiotic regulatory elements in enhancers of target genes. We used series fusion proteins, heterologous DNA-binding domain, study independently trans-activating function human and ARNT proteins yeast. results confirm both contain carboxyl-terminal trans-activation domains. has domain composed...
In recent years, it has become clear that in many proteins, significant regions are encoded by amino acid sequences do not automatically fold into their fully condensed, functional structures. Characterization of the conformational propensities and function nonglobular protein represents a major challenge. Striking among proteins with unfolded numbers transcription factors, including steroid receptors. cases, or partially folded such take shape when interacts its proper binding partner(s),...
Previous deletion analysis localized the major transactivation function of human glucocorticoid receptor to a 185-amino acid segment close N terminus protein. This region was named tau 1 [Hollenberg, S. M. & Evans, R. (1988) Cell 55, 899-906]. To delineate smallest active within 1, we have systematically tested capacity derivatives domain, fused DNA-binding in yeast cells. Internal scanning deletions suggested that residues near C are most important for activity. Deletions N-terminal and...
The androgen receptor (AR) mediates the action of steroid hormones testosterone and dihydrotestosterone. protein contains two globular α-helical domains responsible for binding hormone DNA. In contrast, N-terminal domain is less well structurally defined main determinants receptor-dependent transactivation, termed AF1. Previously, we have shown this region has propensity to form α-helix structure. Significantly, specific targets or a natural osmolyte resulted in more protease resistant...
The androgen receptor (AR) signaling pathway is a major therapeutic target in the treatment of prostate cancer. AR functions as ligand-activated transcription factor presence cognate hormone ligands testosterone and dihydrotestosterone (DHT). We have characterized highly conserved sequence at C-terminal end helix 10/11 ligand-binding domain (LBD), which prone to point mutations This includes threonine 877 that involved hydrogen bonding D ring steroid molecule leads promiscuous ligand...