The development of cancer is due to loss of homeostasis between cell proliferation and cell death. Whilst it has been evident for some time that uncontrolled proliferation occurs in transformed cells, the lack of appropriate cell death is possibly of equal importance. Thus up-regulation of genes that inhibit tumour cells to promote their survival and continued growth. In recent years it has become evident that many cytotoxic agents can induced apoptosis through a number of different pathways that overlap to a greater or less extent, and finally converge on a common set of mediators, a series of proteases called caspases. Proteins that can inhibit one or more pathways of apoptosis have been identified, and some of these are over-expressed in tumour cells. The Bcl-2 homologues and the IAP family of proteins are the two best characterized groups of mammalian apoptosis inhibitors. It is proposed here that heat shock protein 72 (HSP72) can also function as an anti-apoptosis gene and evidence to support this statement is given. It is the aim of this project to determine the range of cytotoxic agents for which HSP72 shows protection and to establish the way in which HSP72 achieves this inhibition of cell death. Using a number of different cell lines expressing varying levels of HSP72, a series of experiments that will achieve this aim will be completed. It is also evident that other inhibitor proteins exist in cells and these may also be exploited by tumours to gain a survival advantage. In part 2 of this project, a screen of a cDNA library will be done to seek novel anti-apoptosis genes. The results of these studies should provide the knowledge required for the development of therapeutic strategies for tumours that develop resistance to apoptosis.
