Tumour suppressor genes act as recessive determinants of cancer. It is recently known that various actin-associated cytoskeletal proteins and structural components of intercellular junctions are encoded by, or are related to products of tumour suppressor genes. Very little is known of how tumour suppressor molecules associate with or function at the cortical membrane skeleton and/or specialised junction domains. To understand the molecular events governing tumour suppressor activity, extensive molecular cell biology studies have to be implemented. This is the major objective of our proposal.
As a choice of tumour suppressor, we will study schwannomin. Schwannomin is the product of the NF2 gene which, when mutated at the germline level, causes neurofibromatosis type 2, a tumour susceptibility disease predisposing mainly to meningiomas and schwannomas. Schwannomin, together with ezrin, radixin, and moesin, comprise the ERM family of membrane cytoskeletal linker proteins. To define the specific activity of schwannomin requires an understanding of the role of each member of the ERM family. Moreover, since ERM proteins are involved in adhesion events that are essential for the control of epithelial cell differentiation and growth, we will also investigate how the assembly of junctional membrane domains, such as tight and adherents junctions, is regulated.
To understand how these various sub-membranous protein complexes function will require us to analyse the multiple interactions that occur between the numerous components involved. Especially, we will investigate how changes in interactions can mediate tumourogenic potential since activation of membrane receptors (notably HGF/SF receptor, the product of the c-met proto-oncogene) can initiate signal transaction via ERM and junctional proteins leading to junction destabilisation, actin microfilament reorganisation and loss of control of cell proliferation.
We will utilise different developmental and cellular models, including Dictyostelium, Xenopus embryos, mouse preimplantation embryos, genetically engineered cell lines, as well as sophisticated in vitro biophysical assays to study the pattern of expression and mode of interaction of tumour suppressor molecules. Modern molecular techniques, using probes generated and shared by participating laboratories, will be used in these experimental systems to modulate, inhibit, delete, rescue or overexposes tumour suppressor proteins, and thereby to gain novel insight into how they function. Our objectives are beyond the capacity of a single research group to achieve. However, the collective breadth and combined expertise of our partnership will enable us to make substantial progress in a synergistic manner and at an accelerated rate of success.
In addition to a detailed understanding of the fundamental mechanisms regulating suppression of cancer in normal cells, one practical benefit of our proposal will be to elucidate the molecular mechanism by which schwannomin is implicated in schwannomas and meningiomas. These two tumour types together represent close to 30 % of all nervous system tumours that develop in humans. Based on this knowledge, it is hoped that new therapeutic approaches may be proposed.
Funding SchemeCSC - Cost-sharing contracts
SO9 3TU Southampton