Professor Iain J McEwan, Institute of Medical Sciences, Office 2.34, School of Medicine, Medical Sciences and Nutrition, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Aberdeen, AB25 2ZD
Iain McEwan graduated with a first in Biochemistry from the University of Strathclyde in 1983, and went on to gain a PhD in 1987 from the University of Glasgow.
From 1986-1989 he worked as a Postdoctoral research fellow at the Friedrich Meischer Institute in Basel, Switzerland. He then moved to Sweden where he gained experience working as a Postdoctoral research fellow at the Karolinska Institute, Stockholm and then as a Junior group leader in the Department of Biosciences at Novum, Karolinska Institute, Stockholm, Sweden.
In 1997 he moved south (!) to take up a lectureship at the University of Aberdeen and in 2003 was made a Senior Lecturer, Reader in 2005 and awarded a Personal Chair in 2009.
The research of my group focuses on investigating the molecular mechanisms of action of the human androgen receptor and translating fundametal descoveries to the clinic. The androgen receptor is an intracellular receptor protein that acts as the 'gatekeeper' for the actions of the male steroid hormones testosterone and dehydrotestosterone. The androgen receptor functions as a liganded-activated transcription factor that both up-and down-regulates networks of genes in target tissues. Mutations in the receptor can lead to a disruption of male development (androgen insensitivity) and a neuromuscular degenerative disorder (Kennedy's disease). Mutations have also been identified in patients with prostate cancer both before and after hormone therapy. It has been proposed that such mutations may influence the effectiveness of androgen ablation therapy and play a role in the progression to hormone-refractory disease.
The androgen receptor is organised into discrete structural and functional domains, consisting of a central DNA binding domain (DBD), flanked by a C-terminal ligand binding domain (LBD), and a structurally distinct N-terminal domain (NTD) important for receptor-dependent transactivation. The androgen receptor can regulate both the initiation and elongation steps of the transcription cycle and we have identified and characterised an interaction between the receptor and the general transcription factor TFIIF, which appears important for the transcription initiation steps (see model). We have also shown that the androgen receptor-transactivation domain folds into a more stable conformation, possibly involving alpha-helix formation, resistant to protease attack, in the presence of the target protein TFIIF or the structure stabilising solutes trimethylene N-oxide (TMAO) and trifluorethanol (TFE). Thus our working hypothesis is that the receptor-NTD is structurally flexible, permitting multiple protein-protein interactions with the transcriptional machinery. Specific protein-protein interactions will induce folding of the receptor-transactivation domain and provide a platform for the assembly of a transcriptionally competent complex, containing basal transcription factors and co-activator proteins (SRC, CBP).
Recently, we have extended these studies to investigate the structure-function of the human mineralocorticoid receptor N-terminal domain. The mineralocorticoid receptor is a risk factor in hypertension, cardiovascular disease and metabolic synodrome. This region has a complex transactivation function consisting of different sub-domains which exhibit different functional and/or structural properties. Current work aims to investigate the translational potential of these studies in the treatment of hormone-dependent diseases.
Several potential PhD project opportunities are available:
- Therapeutic Targeting of the Structurally Plastic N-terminal Domain of Steroid Receptors
- Tissue-selective regulation and expression of the human androgen receptor gene
I am currently accepting PhDs in Biomedical Sciences.
Please get in touch if you would like to discuss your research ideas further.
Current research focuses on two main themes:
1. The expression and control of the androgen receptor gene in male and female tissues, including prostate, bladder and bone. We are also investigating the role of steroid hormones action on immune cell function in health and cancer. These projects are in collaboration with Professor Heather Wilson (IMS https://www.abdn.ac.uk/ims/research/profiles/h.m.wilson) and Professor Philippa Saunders and Dr Douglas Gibson University of Edinburgh.
2. Developing novel therapeutic strategies to switch off androgen receptor function in cancer cells. These projects involve medicinal chemistry approaches to synthesising bespoke small molecule inhibitors and novel biologics called SoloMERs in collaboration with the biopharmaceutical company Elasmogen (https://www.elasmogen.com/about-elasmogen/).
My group collaborates with a number of colleagues in both nationally (UK) and internationally (The Netherlands, Spain and North America). Current interdisplenary collaborative projects focus on mathematical modelling of gene expression and medicinal chemistry. We also have a collaboration with a local biopharmacetical company, called Elasmogen invetigating biologics as novel therapeutics in hormone-dependent cancers.
I have successfully supervised more than 10 PhD students since joining the UNiversity of Aberdeen. I am currently supervising four students: two in their first year; one second year; and one in the final year.
Funding and Grants
Research in my laboratory is currently supported by:
Projects grants from the Prostate Cancer Research Centre (https://www.prostate-cancer-research.org.uk/), the Medical Research Council (DPFS award) (https://mrc.ukri.org/) and Pilot STudy Award from Friends of Anchor (https://www.friendsofanchor.org/).
PhD studentship awards from Cranes (https://www.cranes.org.uk/), EASTBIO-BBSRC (http://www.eastscotbiodtp.ac.uk/) and Aberdeen Cancer PhD programme (https://www.abdn.ac.uk/smmsn/research/biobank-1025.php).
I am course coordinator for Honours Biochemistry Option 1 (BC4014).
Non-course Teaching Responsibilities
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Topological dynamics of an intrinsically disordered N-terminal domain of the human androgen receptorProtein science : a publication of the Protein Society, vol. 31, no. 6, e4334Contributions to Journals: Articles
Development of a high-throughput screening assay for small molecule inhibitors of androgen receptor splice variantsASSAY and Drug Development Technologies, vol. 20, no. 3, pp. 111-124Contributions to Journals: Articles
Androgen receptor signaling: Breaking apart condensatesNature Chemical Biology, vol. 18, pp. 1292-1293Contributions to Journals: Comments and Debates
Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes onCancers, vol. 13, no. 3, 509Contributions to Journals: Review articles
Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate CancerClinical Cancer Research, vol. 25, no. 22, pp. 6764-6780Contributions to Journals: Articles
A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancerOncogene, vol. 38, no. 7, pp. 1136-1150Contributions to Journals: Articles
A New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer ActivityJournal of Medicinal Chemistry, vol. 62, no. 2, pp. 491-511Contributions to Journals: Articles
Androgens and androgen receptor: Above and beyondMolecular and Cellular Endocrinology, vol. 465, pp. 1-3Contributions to Journals: Articles
Tissue control of androgen action: The ups and downs of androgen receptor expressionMolecular and Cellular Endocrinology, vol. 465, pp. 27-35Contributions to Journals: Review articles
Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription RegulatorsStructure, vol. 26, no. 1, pp. 145-152Contributions to Journals: Articles