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Imperial College of Science, Technology and Medicine
Stefan Grimm
Overview
 
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Overview

The focus of our work is a genetic program called apoptosis. Apoptosis is the suicide process that can be induced in eukaryotic cells under certain physiological or pathological circumstances. Previous studies have emphasized its role in such diverse physiological processes as embryogenesis, tissue homeostasis and immune responses. Some pathological developments e.g. tumourigenesis can be attributed to a reduced apoptosis. Consequently, apoptosis induction must be tightly regulated and should be activated only under certain defined conditions. As apoptosis is genetically regulated many efforts have been made to isolate the components of the apoptosis signalling pathways. Our own approach was motivated by a conspicuous correlation: Most of the genes involved in apoptosis exert their activity upon over-expression. This capacity is even conserved across species boundaries. It might be explained by the observation that apoptosis is mediated by specific protein-protein interactions which are induced when one of the partners is overexpressed. At first, it seemed impractical to use this dominant effect for isolating such genes because their activity leads to cell death instead of cell proliferation as in the case of oncogenes. However, we have been able to isolate such dominant, apoptosis-inducing genes. To this end we developed a genetic high-throughput screen to isolate dominant apoptosis-inducing genes: the typical apoptosis phenotype is observed with phase contrast microscopy after multiple parallel DNA-transfections of individual expression plasmids in a 96-well format. Among the isolated genes are several genes that are already known as apoptosis inducers and therefore serve as positive controls. Apoptosis induction calls for the transformation of the original signal, by means of a signal transduction pathway, in the activation of proteases, the so-called caspases, which initiate the process of self-destruction. The aim of our project is to use the isolated genes to define apoptosis sensors in the cell, characterise the activated signal transduction pathways and study their role in tumourigenesis.

 


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