The p53 tumour suppressor network
Division of Cancer Research
Jacqui Wood Cancer Centre
University of Dundee
James Arrott Drive
Ninewells Hospital And Medical School
+(44) 01382 383215
David Meek obtained his PhD from the University of Glasgow in 1983 where he studied the regulation of gluconeogenesis by protein phosphorylation and by the novel metabolic regulator, fructose 2,6-bisphosphate, in Hugh Nimmo’s lab. He subsequently won an MRC Retraining Fellowship in Recombinant DNA Technology which he took up at the Department of Molecular Biology in the University of Edinburgh. Here he studied the regulation of expression of RNA polymerase in E. coli under the direction of Richard Hayward. David then carried out four years’ post-doctoral study at the Salk Institute in San Diego, funded by a fellowship from the American Cancer Society. He worked under the direction of Walter Eckhart and pioneered our understanding of the regulation of the p53 tumour suppressor by post-translational modification. David returned to the UK in 1990 having obtained a prestigious MRC Senior Fellowship to work in the MRC Protein Phosphorylation Unit at Dundee. Here he developed his research programme as an independent researcher with the enthusiastic support of Prof Sir Philip Cohen and Prof Sir David Lane. During this time David made a number of key contributions to our understanding of p53 regulation and opened up an area of study that was subsequently to attract intensive international interest and effort. In 1993 he moved to the fledgling Biomedical Research Centre at Ninewells Hospital where he continued to develop his interest in the p53 pathway and maintain his collaborative association with basic scientists and clinicians. He continued to be supported here by the MRC fellowship which he held until 2001. In 1996 he jointly organised and hosted the 8th International p53 workshop at Dundee, together with David Lane and Peter Hall. This event brought together the leading international pioneers of p53 research at what is now the major international p53 conference series: it also underpinned the collective focus, strength and success of p53 research across Dundee. At the beginning of the new millennium David pioneered our understanding of the regulation of MDM2, the key regulator of p53, by post-tranlsational modification. This gave rise to an international effort in this area and provided a major focus of his research activities for the next 6-7 years. Together with David Lane, he instituted the first International MDM2 Workshop at Dundee which was to become a major two-yearly international event held at various prestigious centres across the globe. David continues his interest in the p53 network where his efforts have focused on its role in human cancer and its potential for reactivation as a therapeutic strategy to combat cancer.
The p53 tumour suppressor protein is a potent transcription factor which stimulates the expression of a host of genes involved in growth arrest, apoptosis, DNA repair, metabolism, stem cell renewal, inhibition of angiogenesis, invasion and metastasis. p53 also is able to repress the expression of a different set of genes including those involved in mediating or stimulating cell division. These events are thought to mediate p53 tumour suppression function. Loss of p53 activity in developing cancers occurs through various mechanisms, including mutation of the TP53 gene itself (encoding p53), and leads to loss of tumour suppressor function. Additionally, several commonly occurring TP53 mutations give rise to so-called “gain-of-function” mutant p53 proteins that have acquired new activities thought to help drive aggressive cancer behaviour.
Aims of our Research
• To understand the molecular basis of the signalling mechanisms (post-translational modifications and protein:protein interactions) that regulate the p53 response.
• To determine whether the signalling events regulating p53 are modulated or changed during tumorur development in a manner that would inhibit the ability of the p53 network to carry out its protective function of eliminating genetically damaged cells.
• To explore specific mechanistic and signalling interactions with a view to determining their potential as targets for novel therapeutic intervention in the treatment of cancer.
· Holly B. Kramer, Chun-Fui Lai, Hetal Patel, Manikandan Periyasamy, Meng-Lay Lin, Stephan M. Feller, Frances V. Fuller-Pace, David W. Meek, Simak Ali, Laki Buluwela. (2016) LRH-1 regulation of CDKN1A gene expression in colon cancer cells by modulation of p53. Nucleic Acids Res, 44, 582–594.
· Marcar L, B Ihrig, SE Bray, PR Quinlan, L Jordan, AM Thompson, TR Hupp and DW Meek. (2015) MAGE-A Cancer/Testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4. PLOS ONE, DOI:10.1371/journal.pone.0127713.
· Loughery J, M Cox, L M Smith and DW Meek. (2014) Crucial role for p53-Serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters. Nucleic Acids Res, 42, 7666-7680. Published as a "Breakthrough" article by the journal.
· Iyer S, S Nicol, P Quinlan, A Thompson, D Meek and F Fuller-Pace. (2014) The RNA helicase/transcriptional co-regulator, p68 (DDX5), stimulates expression of the oncogenic protein kinase, PLK1, and is associated with elevated PLK1 levels in human breast cancers. Cell Cycle, 13, 1413-1423.
· Nicol SM, SE Bray, HD Black, SA Lorimore, EG Wright, DP Lane, DW Meek, PJ Coates, FV Fuller-Pace. (2013) The RNA helicase p68 (DDX5) is selectively required for the induction of p53-dependent p21 expression andcell-cycle arrest after DNA damage. Oncogene, 32, 3461-3469 doi: 10.1038/onc.2012.426.
· King SI, S Bray, PR Quinlan, L Jordan, CA Purdie, AM Thompson, and DW Meek. Histological detection of PLK1 in primary breast cancer is associated with TP53 mutation and denotes poor clinical outcome. (2012) Breast Cancer Res, 14 R40.
· Marcar L, NJ MacLaine, TR Hupp and DW Meek. (2010) The Mage-A family of cancer/testis antigens inhibits p53 function by blocking its interaction with chromatin. Cancer Res, 70, 10362-10370.
· McKenzie L, S I King, L Marcar, S Nicol, SS Dias, K Schumm, P Robertson, J-C Bourdon, N Perkins, F Fuller-Pace and DW Meek. (2010) p53-dependent repression of polo-like kinase-1 (PLK1). Cell Cycle, 9, 4200-4212.
· Lai KP, Leong WF, Chau JF, Jia D, Zeng L, Liu H, He L, Hao A, Zhang H, Meek D, Velagapudi C, Habib SL, Li B. (2010) S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. EMBO J. 29, 2994-3006.
· M Cox and DW Meek. (2010) Phosphorylation of serine 392 in p53 is a common and integral event during p53 induction by diverse stimuli. Cell. Signal., 22, 564-571
· Meek, DW. (2015) Regulation of the p53 response and its relationship to cancer. Biochem J, 469, 325-346
· Loughery J and D W Meek. (2013) Switching on p53: an essential role for protein phosphorylation? Biodiscovery, 8, 1: DOI 10.7750/BioDiscovery.2013.8.1
· Meek DW and L Marcar. (2012) MAGE antigens as targets in tumor therapy. Cancer Lett, 324, 126-132.
· Meek DW and TR Hupp (2010) The Regulation of MDM2 by multisite phosphorylation – opportunities for molecular-based intervention to target tumours? Semin Cancer Biol 20, 19-28.
· Meek, D.W. and Anderson, C.W. (2009) Post-translational modification of p53: Cooperative integrators of function. Cold Spring Harb Perspect Biol:a000950. Epub 2009 Oct 28
· Meek, D.W. (2009) Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer, 9, 714-723.
RECENT BOOK CHAPTERS
· Meek DW. (2012) MDM2. In "Encyclopaedia of Cancer", 4th edition, ed Schwab M. Pub online.
· Meek, DW. (2012) Protein kinase CK2 and the p53 pathway. In: "Protein kinase CK2". The Wiley-IUBMB Series on Biochemistry and Molecular Biology, ed. Pinna L. pp190-199.
David Meek teaches, and has taught previously, on several courses in the Medical School including: BMSc (bachelor of medical science); MB ChB student-selected components; the MRes Cancer Biology (post-graduate) course; and the BSc Biomedical Sciences course (Schools of Life Sciences, and Medicine). He additionally runs a level 3 BSc (Biomedical Science) module entitled: "Cell proliferation and survival mechanisms underlying disease" and a post-graduate MRes Cancer Biology module entitled: "Scientific Method".
At the postgraduate level he has trained 5 MRes students, 1 MSc (by research) student and 11 PhD students. He currently has 5 PhD students under his supervision. David is the Deputy Chair of the Research Postgraduate Committee in the Medical School. He is also a leading player in several other committees that oversee teaching quality, organisation and funding in the university.
Bianca Ihrig, Disruption of Mage-A/p53 association as therapeutic strategy for breast cancer, began 2013.
Sumanth Iyer, 'Regulation of the PIM oncogene interaction', began 2013.
Linda Smith, 'Influence of P53 pathway in determinig efficacy or toxicity of treatment with novel polo-like kinase-1 (PLK1) targeted anti-cancer therapeutic agents', began 2014.
Anna Estevan Barber, Activation of "gain-of-function" mutant p53 by chemotherapeutic drugs in breast cancer progression: mechanism and implications for choice of treatment,' began 2014
Maryam Ahmadi, Regulation of PLK1 Expression by p53 and by Cell Cycle Periodicity, began 2015
David Meek has given over 30 invited seminars in the UK, continental Europe, the USA and the far east. He has also been an invited speaker at more than 40 international events including recent deliveries at the 14th and 15th International p53 Workshops at Shanghai and Philadelphia respectively, the International protein kinase CK2 Conference at Cologne in Germany, and the 1st Australian p53 Workshop held in Melbourne.
Alumni of the Meek lab are as follows:
Rhiannon Williams - MRes student, Jan-Aug, 2013
Sumanth Iyer - PhD student, Oct 2012 - present
Bianca Ihrig - PhD student, Oct 2012 - present
Jeremy Duval - Erasmus student, April-Aug, 2012
Kerry Drysdale - MRes student, Jan-Aug, 2012
Andreas Zimmer - Erasmus student Nov 2011-May 2012
Harpal Saundh - MRes student, Jan –Aug 2011
Jayne Loughery - Post-doc, since Jan 2011
Sharon King (Fury) - Post-doc, since June 2008 (Sharon received the Sir Alastair Currie Award from the Pathological Society of Great Britain and Ireland (2010) for the work she carried out in the Meek lab)
Miranda Cox - PhD student, Oct 2007 – Nov 2010
Lynnette Marcar - PhD student, 2006-2009 and post-doc, 2009-2012 (Lynnette was awarded the Howard-Elder prize for the research she carried out in the Meek lab.)
Lynsey Mackenzie - PhD student, Sept 2006 – Sept 2010
Caroline Hutchinson - BMSc student, 2005.
Anna Maria Ochocka - Post-doctoral assistant, February, 2005 – January, 2008
Marina Bjorling-Poulsen - Visiting graduate student from Denmark, September – December, 2003
Carol Hogan - PhD student, October, 2003 – July 2007
Heather McCallum - Medical student (May - June, 2003)
Nerea Allende-Vega- Post-doctoral assistant, April 2003 – March 2006
Petros Kampanis - Ph.D. student, October 2001-April 2005
Sylvia Dias - Ph.D. student, October 2000-December 2003. Subsequently post doc January 2004 – March 2007
Magdalena Pyrz - Visiting student from Denmark, February 2000 – July 2000
Catherine Meplan - Post-doctoral fellow. January 2000-December 2002
Anthea Martin - Ph.D. student. November 1999-December 2002
Majbrit Hjerrild - Visiting student from Denmark, October 1999 - February 2000
Jim Sillibourne - Post-doctoral Fellow. February, 1999 – January 2001
Severine Seemann - Summer Student, 1998.
Paul Looby - Ph.D. student. October, 1997 – November, 2001
Nicolas Dumaz - Post-doctoral Fellow. August 1997 – July 2000
Niamh Sheridan - BSc (Hons) student. October, 1996 - March 1997
Trevor Hay - Post-doctoral Fellow. March, 1997 – February, 2000.
Uwe Knippschild - Post-doctoral Fellow. April 1995- December 1997. (Uwe was awarded the Howard-Elder prize for the research he carried out in the Meek lab.)
Lesley Jardine - BSc (Hons) student and Ph.D. student. October 1995 - May, 1999.
Linda Woodford - Ph.D. student. 1992-1996. (Mckendrick)
Sue Hall - Ph.D. student. 1992-1995.
Linda Campbell - Technician, 1993-1997.
Ruth Palmer - BSc (Hons) and Summer student, 1991.
Diane Milne - Scientific Officer and (part-time, 1991-1995) M.Sc. student. 1990-2006.