Programmed Cell Death
DR LUMINITA PARAOAN
MEET THE FULL TEAM
Meet the members of the Ocular Molecular Biology Group at the University of Liverpool.
PROJECT TITLE: In vitro study of molecular mechanisms of cell death and cell adhesion mediated by the p53 effector PERP
PROJECT TIMESCALE: 3 years – 12 December 2008 – 11 Dececmber 2011
POST DOCTORAL RESEARCHER: Dr Lyndsay Davies
UPDATE MAY 2012 – CONTROLLING THE CONTROLLER
Unveiling intricacies of programmed cell death
Funding from The Humane Research Trust is enabling a new line of research into mechanisms controlling the fine balance between cell death and survival. The research is undertaken in the Ophthalmology Research Unit, University of Liverpool making use of specific eye cells as an experimental model of a cell death pathway that plays a role in cancer development
Over the last three years we have developed and applied an in vitro experimental system to unveil specific steps of a mechanism used by cells to control their survival or death. Programmed cell death, also known in scientific terms as apoptosis, is a vital process which cells engage with either in relation to normal development (such as formation of organs) or for safe removal of abnormal/damaged cells from the body. In cancer, the mechanism of apoptosis is often faulty, frequently due to mutations or loss of genes that normally function to promote cell death, thus leading to uncontrolled growth of abnormal cells.
Fig 1 :
Caught in the act: Cell undergoing programmed cell death (apoptosis) following induction by PERP – a major pro-apoptotic effector in uveal melanoma. Live cells making a green fluorescently-labelled PERP protein localized at the cell membrane (boundary of the cell) were studied to characterize key features of apoptosis and its regulation.
Our studies were initially concerned with the control of programmed cell death in uveal melanoma (an adult eye cancer) as we identified a key pathway for controlling the death of these cells. However, the progress we made allowed us to reveal characteristics of this process which are relevant for other types of cancer as well.
Following the discovery that the aggressive type of uveal melanoma escapes the control of programmed cell death by significantly reducing the level of a protein (called PERP) that functions to ‘push’ cells into death, our lab embarked in characterizing how this is happening. Dr Lyndsay Davies, a post-doctoral researcher funded by The Humane Research Trust, investigated the significance of different PERP protein levels for the resistance of cancer cells to undergo cell death, how the protein levels can be influenced and what functional partners does PERP have in this process. One of the novel findings was that PERP forms part of a positive feedback loop in which it influences its own key regulator, the major tumour suppressor p53.
Cells having increased levels of PERP (green) die through apoptosis (rounded up cells, shown by different markers, blue and red), while the cells that lack or have less PERP (seen in the phase image) are not eliminated through this process.
In addition to peer-reviewed publications, the findings have been and are due to be presented at prestigious international meetings, most notably at the 4th Annual World Cancer Congress 2011 and The International Society for Eye Research, Berlin 2012 in a session dedicated to Contribution of Apoptosis to the Biology of Retinal Cells in Health and Disease.
Our long term aim is to contribute to the understanding of the processes that allow cells to survive or die. The specific studies of the PERP contribution to the mechanism of cell death may reveal novel targets that could be exploited for the development of therapies that increase the ability of diseased cells to die.
Lab meeting of the Ocular Molecular Biology and Mechanisms of Disease Group (Group leader Dr Luminita Paraoan). Apoptosis is one of the main research areas of interest and expertise in the group.
The generous support of The Humane Research Trust for our research is gratefully acknowledged.