Newcastle University

Qualifications

PhD 2006 E. L. Clark 'Topoisomerase II alpha genomic DNA binding sites' Institute of Cell & Molecular Biosciences, Newcastle University, UK

BSc 1999 (Hons) Biochemistry with industrial placement (FSS, Birmingham) University of Sussex, UK

Previous Positions

2002-2006 BBSRC (GSK Case) PhD Student - Institute of Cell & Molecular Biosciences, Newcastle University, UK

2001-2002 Research Assistant - Dept. of Fetal Medicine, Birmingham Womens Hospital, UK

1999-2001 Graduate Pharmaceutical Scientific Researcher - Roche, Welwyn Garden City, UK

1997-1998 Industrial Studentship Placement - Home Office Forensic Science Service, Birmingham, UK

Memberships

BACR

Honours and Awards

2008 - Awarded BACR Scholarship (£1k) to present research at Keystone Conference, USA

2007 - Winner of Newcastle University Postdoctoral Career Pathways Scheme Poster prize

2006 - Winner of the Science & Technology Achievement Category of Newcastle University Enterprise Challenge Business Plan Awards, sponsored by Muckle LLP

Research Interests

Research Interests:
p68 DEAD Box RNA Helicase (DdX5) cellular function.
Androgen Receptor (AR) transcriptional control - co-regulatory mechanisms.
Molecular biology of hormone escape in Prostate Cancer (PCa).
Use of Tyrosine Kinase Inhibitors PCa.

Main expertise:
Chromatin Immunoprecipitation
siRNA & shRNA gene expression knockdown
Real-time PCR
RNA isolation for expression analysis
Reporter Assays
Mammalian Cell Culture
Routine Molecular Biology Techniques

Other Expertise

Antibody production and purification
Confocal Microscopy and Immunofluorescence
Tissue Microarray Staining
Minigene Splicing Assays
Establishing Stable Cell lines

Topoisomerase II drug poisoning
Cytotoxicity Assays
Genomic Microarray Bioinformatic analysis
FACS
Trapped in agarose DNA immunostaining (TARDIS)

Current Work

Identifying co-regulators of the AR that influence the development of hormone escape for PCa is important in the development of effective therapies and prevention of hormone refractory prostate cancer (HRPCa). We identified the DEAD box RNA helicase p68 (DdX5) as a novel co-activator of AR regulated transcriptional activity. Additionally, we found that p68 potentiates AR-regulated repression of splicing of a hormone responsive CD44 variable exon minigene, underscoring an effect of p68 on AR dependent splicing via transcriptional co-regulatory mechanisms. These findings suggest that p68 may function as an ‘adaptor’ or ‘coupling’ protein that coordinates the tightly integrated processes of transcription and mRNA processing. Mechanistically, it would be logical that the AR interacts with a cofactor linked to all steps from transcription to transcript release, facilitating the efficacy of AR mediated gene transcriptional elongation. We have further shown that p68 is over-expressed in PCa, and c-Abl kinase activity enhances AR co-activation specifically through the tyrosine phosphorylation of p68 at Y593. Collectively these findings indicate that p68 may play a significant role in PCa progression to androgen independence, and posttranslational modifications of p68 may be important in tumour development and progression to HRPCa. This work has been facilitated by successful collaborations with Dr. Frances Fuller-Pace (University of Dundee, UK) and Dr. David Elliot (Newcastle University, UK).

Future Research

C-Abl tyrosine kinase inhibitors such as Imatinib (ST-1571) and Nilotinib (AMN-107) may be of therapeutic benefit if post-translational modifications are shown to be important in modulating p68 function and affect disease phenotypes. Future research aims to elucidate the mechanisms by which activation of c-Abl mediated tyrosine phosphorylation of p68 contributes to androgen receptor-regulated transcriptional activity in prostate cancer (PCa) and progression to hormone refractory prostate cancer (HRPCa).

Esteem Indicators

2008 (May) - Invited Speaker at Northern Collaborative ProMPT meeting, CRUK Cambridge Research Institute (CRI), Cambridge, UK

2008 (Jan) - Invited Speaker at RNA UK meeting, Burnside Hotel, Lake District, UK

Funding 

Prostate Action funded grant (Assessing RNA helicase p68 (Ddx5) as a biomarker in the deregulation of microRNAs in Prostate Cancer - £99,987) awarded to Dr. E. L. Clark and Prof. C. N. Robson (Jan 2012-Oct 2013)

Prostate Cancer Research Foundation (PCRF) funded grant (Pharmacological perturbation of p68 - an important androgen receptor transcriptional co-regulator in prostate cancer - £99,941) awarded to Dr. E. L. Clark and Prof. C. N. Robson (Jan 2008- Dec 2011)

Grant funding cited in local newspapers: Weds Oct 29th 2008 Sunderland Echo ‘In brief-Cancer Cash’, Tues Oct 28th 2008 Evening Chronicle ‘£100,000 to help in fight against Cancer’ and Mon Nov 24th The Journal ‘£100,000 for cancer team’.

Industrial Relevance

1999 - 2001 Graduate Pharmaceutical Scientific Researcher
Roche, Welwyn Garden City, UK

Completed a multidiscipline graduate research-training programme within a drug discovery centre of excellence. Gained a complex, practical knowledge of a wide range of scientific techniques routinely applied to the pharmaceutical drug discovery industry.

Undergraduate Teaching

Demonstrator, tutor, seminar leader and lab project supervisor for undergraduates in bioscience discipline

Postgraduate Teaching

Supervise MRes and PhD project students in the lab

• Rajan P, Dalgliesh C, Bourgeois CF, Heiner M, Emami K, Clark EL, Bindereif A, Stevenin J, Robson CN, Leung HY, Elliott DJ. Proteomic identification of heterogeneous nuclear ribonucleoprotein L as a novel component of SLM/Sam68 Nuclear Bodies. BMC Cell Biology 2009,10 1 82.
• Clark EL, Coulson AC, Dalgliesh C, Rajan P, Nicol SM, Fleming S, Heer R, Gaughan L, Leung HY, Elliott DJ, Fuller-Pace FV, Robson CN. The RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer. Cancer Research 2008, 68(19), 7938-7946.
• Clark EL, Fuller-Pace FV, Elliott DJ, Robson CN. Coupling transcription to RNA processing via the p68 DEAD box RNA helicase androgen receptor co-activator in prostate cancer. Biochemical Society Transactions 2008, 36(3), 546-547.
• McComb CM, Clark EL, Padget K, Harvey J, Morris NJ, Austin CA. Bioinformatic analysis of topoisomerase II binding sites. In: 30th Annual Meeting of the United Kingdom Environmental Mutagen Society. 2007, University of Cardiff, UK: Mutagenesis: Oxford University Press.
• Clark EL. Topoisomerase IIa human genomic binding sites. Newcastle upon Tyne: University of Newcastle upon Tyne, 2006.
• Kilby MD, Barber K, Hobbs E, Franklyn JA. Thyroid hormone action in the placenta. Placenta 2005, 26(2-3), 105-113.
• Chan S, Kachilele S, Hobbs E, Bulmer JN, Boelaert K, McCabe C, Driver P, Bradwell A, Kester M, Visser T, Franklyn J, Kilby M. Placental iodothyronine deiodinase expression in normal and growth-restricted human pregnancies. Journal of Clinical Endocrinology and Metabolism 2003, 88(9), 4488-4495.