Cell Death and Survival
DR LUMINITA PARAOAN
PROJECT TITLE: Investigation of molecular interactions and mechanism of action of p53/PERP pathway in cancer and non-cancer cell models
PROJECT TIMESCALE: 3 years – 1 February 2013 to 30 Sept 2016
POST-DOCTORAL RESEARCHER: Dr Raheela Awais
LIVING ON THE EDGE: HOW DO CELLS MAKE THE DECISION BETWEEN SURVIVAL OR DEATH
Funding from The Humane Research Trust is supporting a specific line of research in our group concerned with the characterization of the mechanisms that control the fine balance between cell death and survival. We are developing and using in vitro experimental models that help us dissect the functioning of a pathway with a central role in the cell’s decision towards its survival, both in normal health, and in diseases as varied as cancer and age-related macular degeneration.
Cells are equipped with mechanisms that allow them to respond when they are damaged, aged or not functioning properly; they can either be repaired or removed. In addition, in the normal development of organs for example, some cells are not needed at some stages. The process by which cells are safely removed in such instances is called programmed cell death or apoptosis. This is a highly organized and regulated process that is critical for the good functioning of cells, organs and organisms. It is also very important for preventing cells with defects from multiplying and limiting further damage that can lead to uncontrolled cell growth and the development of cancer. In cancer, the mechanism of apoptosis is often faulty, frequently due to mutations or loss of genes that normally function to promote cell death. This also makes cancer cells more difficult to destroy, since many anti-cancer drugs and treatments work by promoting the diseased cells to undergo cell death. Consequently, cancer cells which cannot engage in this process are often resistant to these drugs.
The control of such complex processes in the cells is achieved by the interaction and association of many different proteins and molecules. Removal or modification of just one of these components can lead to disruption of the whole process.
Our studies in this area focussed initially on 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. One of our key findings to date is that a group of the proteins with essential roles in this signalling work in a positive feedback loop, that is to say that they control and enhance the activity among themselves. These results not only explain some of the features of the disease process, but also may direct future studies aiming to develop therapies that increase the ability of diseased cells to die. Currently we are expanding the experimental systems that are used to interrogate in detail the specifics of this process in other ocular cells and non-ocular cancer cells.
In the longer term, we believe that our investigations will provide further understanding of the intricacies of signaling in the process of deciding between survival/repair and death of cells.
The specific studies of thePERP 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.
The Humane Research Trust is a key supporter of our successful line of investigation into apoptosis. The link between our group and the Trust has been further strengthened by the recent appointment of Dr Raheela Awais, who will apply her combined experience in molecular biology and cellular imaging to the study. The continued support of the Trust for our research is gratefully acknowledged.