INHIBITION OF CASPASE-3 AS A NEW THERAPEUTIC APPROACH IN
L.Flanagan, S.Curry, M. Meyer, J. Fay, O. Bacon, E.W. Kay, D.A. McNamara, and J.H.M. Prehn
‘’We examined the role of executioner caspases in tissue regeneration following chemotherapy.Exploiting and antagonising this paracrine role of executioner caspases may be an interesting, novel approach for the treatment of tumours characterised by
resistance and relapse. Our data highlight that inhibition of Caspase-3, or
antagonising downstream effectors of Caspase-3 paracrine signalling, may
represent a novel approach to halt, or at least impede, tumour cell repopulation
The protease caspase-9 is activated on the apoptosome, a multi-protein signal transduction platform that assembles in response to mitochondria-dependent apoptosis initiation. Despite extensive molecular research, the assembly of the holo-apoptosome and the process of caspase-9 activation remain incompletely understood. Here we therefore integrated quantitative data on the molecular interactions and proteolytic processes during apoptosome formation and apoptosis execution, and conducted mathematical simulations to investigate the resulting biochemical signalling, quantitatively and kinetically.
Interestingly, when implementing the homo-dimerisation of procaspase-9 as a prerequisite for activation, the calculated kinetics of apoptosis execution and the efficacy of caspase-3 activation failed to replicate experimental data. In contrast, assuming a scenario in which procaspase-9 is activated allosterically upon binding to the apoptosome backbone, the mathematical simulations quantitatively and kinetically reproduced all experimental data. These data included a XIAP threshold concentration at which apoptosis execution is suppressed in HeLa cervical cancer cells, half-times of procaspase-9 processing, as well as the molecular timer function of the apoptosome.
Our study therefore provides novel mechanistic insight into apoptosome-dependent apoptosis execution and suggests that caspase-9 is activated allosterically by binding to the apoptosome backbone. Our findings challenge the currently prevailing dogma that all initiator procaspases require homo-dimerisation for activation.
J Biol Chem. 2014 Aug 8. pii: jbc.M114.590034. [Epub ahead of print]
A systems biological analysis of apoptosome formation and apoptosis execution supports allosteric procaspase-9 activation.
Würstle ML(1), Rehm M(2).
(1)Royal College of Surgeons in Ireland, Ireland.
(2)Royal College of Surgeons in Ireland, Ireland firstname.lastname@example.org
The Centre for Systems Medicine is delighted to announce another speaker to its 2015 seminar series:
Prof. Sergio T. Ferreira.
Professor of Biophysics,Biochemistry, and Neuroscience,
Institute of Biophysics Carlos Chagas Filho & Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio
Venue: Albert Lecture Theatre, RCSI, 9am Friday 27th February 2015
Lecture entitled: ‘”Abetaoligomers and brain inflammation link synapse failure to neuronal insulinresistance and depression in Alzheimer’s disease”
Prof. Ferreira has over 15 years extensive experience in investigating molecular and cellular mechanisms leading to synapse failure and memory loss in Alzheimer’s disease.His main research focus has been on understanding intracellular signaling pathways disrupted or altered when neurons are exposed to Ab oligomers, both in vitro and in vivo.
With particular interest in mechanisms leading to mood alterations in AD and in
shared mechanisms of pathogenesis between AD and diabetes. http://www2.bioqmed.ufrj.br/ldn/sergio.html
All very welcome to attend,
Prof. Jochen Prehn
Cancer Research – Past, Present and Future. Leading Irish and International scientists discuss how cancer research and treatment has evolved in recent years, and what the future holds.
Systems Medicine symposium, BREAST-PREDICT,Irish Cancer
Society Collaborative Cancer Research Centre marking World Cancer Day, 4th February 2015.
The Centre for
Systems Medicine is delighted to announce another speaker to its 2015 seminar
Prof. Graeme Bell
University of Chicago
Houston Lecture Theatre, RCSI, 4.30pm Thursday 22nd January 2015
entitled: ‘Genetics of Diabetes’
Dr. Bell’s research
focuses on the genetics of diabetes mellitus and the biology of the
insulin-secreting pancreatic beta-cell.
He and his colleagues
are using various genetic approaches to map and identify the genes that affect
development of type 2 diabetes mellitus as well as diabetic complications. They
carry out studies in both humans and mouse models to determine the mechanisms
by which the diabetes genes they identify affect blood glucose levels. Their
studies of pancreatic beta-cells are focused on understanding the
transcriptional regulatory networks that determine normal cell function.
All very welcome to
attend, Prof. Jochen Prehn
The Centre for Systems Medicine is pleased to announce
another speaker to our seminar series.
Dr. Maciej Dobrzynski
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4
insights into population-level heterogeneity with examples of MAPK, HIF
response and ubiquitination systems
Venue: Nightingale Theatre, Thursday 15th
Jan 2015 4pm.
All welcome to attend,
Prof. Jochen Prehn
The CASyM roadmap is published
After a two year cross-disciplinary consultation process, the Coordinating Action Systems Medicine (CASyM) has published its European implementation strategy (roadmap) for Systems Medicine. The vision of this roadmap is to develop Systems Medicine into a practical framework that assists clinical decision making and the design of personalised prevention and treatment plans. Central to this is a systems approach that addresses clinical questions and provides solutions to the most pressing clinical challenges such as the results of an ageing population, increased needs for social care and a growing burden of curing and caring for patients with cancer. The roadmap which was authored and reviewed by multiple European academic and industry partners, including Prof. Jochen Prehn, Director of the Centre for Systems Medicine (RCSI), is available for download below:
Friday 5th December 2014, at 2.00 pm
Decisions, decisions: Regulation of apoptotic and necroptotic
cell death in skin cancer
Dr Martin Leverkus
Section for Molecular Dermatology, Department of Dermatology and
Allergology, Medical Faculty Mannheim, University of Heidelberg, Germany.
The Centre for Systems Medicine is pleased to announce another speaker of our seminar series.
Dr Leverkus’s research
is focussed on studying regulation of cell death in the skin under
physiological and pathophysiological conditions, in particular in skin cancer
cells. Specifically, his research is focussed on signalling platforms that
regulate decision processes in cell death research (Feoktistova et al, Mol CELL
2011; Panayotova-Dimitrova et al, CELL Reports 2013) as well as the impact of
small molecule inhibitors of cell death pathways (Geserick et al, Cell Death
& Disease 2014).
The talk will be held in the Houston
Lecture Theatre at 2.00pm 5th
You are all very welcome to attend.
Regards, Markus Rehm
Albert Lecture Theatre, 4pm, Tuesday 28th of October 2014.
James D. Johnson, Ph.D.
Oxford University Visiting Professor of Integrated Physiology, OCDEM/WTCHG,Visiting Fellow of Harris-Manchester College Associate Professor | Medicine |
Cellular and Physiological Sciences, Surgery Diabetes Research Group, Cardiovascular Research Group The University of British Columbia| Canada
Jim Johnson is Associate Professor in the
Department of Cellular and Physiological Sciences and Department of Surgery at
the University of British Columbia. He is a founding member of the Diabetes
Research Group at the Life Sciences Institute at UBC. He is Editor-in-Chief of
the journal Islets, and on the Editorial Board of Diabetes and Endocrinology.
An expert in the fundamental biology of diabetes and related conditions, he is
the author of over 93 peer-reviewed articles since 2000. His work has been
published in some of the most prestigious and highly cited journals including Cell
Metabolism, Diabetes, Diabetologia, Endocrinology, PNAS, Nature Medicine.
His current research focuses on multiple
themes, including: type 1 diabetes, type 2 diabetes, obesity, heart disease,
neuroscience, pancreatic cancer, and longevity. He teaches human physiology to
large and small classes and directly mentors ~12 students and 5 post-doctoral
fellows in his laboratory. The work of his team involves a multidisciplinary
approach. His work has been funded by the JDRF, the Canadian Institutes of
Health Research, the Canadian Diabetes Association, the Stem Cell Network, the
Cancer Research Society, the Canada Foundation for Innovation, and other agencies.
We are delighted to welcome Prof. Johnson to RCSI and the Centre for Systems
Medicine and all very welcome to attend,
Prof. Jochen Prehn
Exploiting addiction to apoptosis inhibitors in cancer
Speaker: Dr Daniel Longley, Centre for Cancer Research and Cell Biology, Queen’s University Belfast
Monday 6th October 2014, at 4.00 pm
The Centre for Systems Medicine is pleased to announce another speaker of our seminar series, Dr Daniel Longley.
Dr Longley’s research is focussed on overcoming drug resistance by activating cell death (apoptosis) in cancer cells. Specifically, his research is centred on the
pre-clinical and clinical development of small molecule inhibitors of
anti-apoptotic proteins, including novel drug delivery strategies, and the
identification of predictive biomarkers to enable the targeted use of novel
anti-cancer therapeutics in molecularly-defined patient populations.
The talk will be held in the Cheyne Lecture Theatre at 4.00pm 6th October 2014.
You are all very welcome to attend.
Centre for Systems Medicine