Hime Lab ~ Project 2

Analysing oncogene / tumour suppressor gene function in Drosophila

Investigators:

Dr. Hannah Robertson (Rm E640, 8344-5779)

Dr Gary Hime (Rm E719, 8344-5796)

How do oncogenes cooperate to cause cancer?

How might we discover new oncogenes?

Can we use genes to control or prevent cancer?

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The Cbl proto-oncogene

One of the major areas of research in our lab is in the investigation of the Drosophila member of the Cbl family of proto-oncogenes, D-cbl. We are interested in D-cbl in two ways: first, we are interested in understanding the normal cellular function of this oncogene family and how that relates to cbl's ability to cause cancer, and second, we are using D-cbl as an entry point into investigating some very basic questions of cancer biology. There are opportunities for projects in both these areas.

The normal function of D-cbl: The cbl family of proteins includes members from mammals, Drosophila and C. elegans . Biochemical investigation of these family members has lead to the identification of a number of proteins that interact with cbl proteins and facilitate the two main biochemical functions of the protein family. The first of these is regulation of targeted ubiquitination (a post-translation protein modification) and degradation of activated tyrosine kinases. The second is transport of complexes containing these kinases from the cell surface through the endosome and to the lysosome where they are degraded. Thus, the cbl proteins are quite well characterised biochemically. What is still not known, however, is what exactly are the cellular consequences of cbl-mediated regulation and how this relates to the cancer-causing potential of cbl mutations. We are using the powerful genetic and cell biological tools available in Drosophila to address this question. There are two different protein isoforms in Drosophila , and several different oncogenic mutations in cbl and we are particularly interested in the functional differences among these different isoforms and mutations.

Caption

We are also conducting an extensive genetic screen to identify other genes that can cooperate with Dv-cbl, one of the oncogenic forms of this gene, to cause tumours. It is known that it requires mutations in more than one gene to produce a tumour, but it is also known that along the way to becoming a tumour, cells accumulate many other, non-contributing, mutations. It is therefore difficult to determine which of the many mutations are actually required for the tumour to develop. In Drosophila , we have the tools to introduce specific combinations of mutations and assess which of these combinations cause tumours and which don't. This project has also led to the identification of novel candidate oncogenes and we are now searching for human homologues of these.

We have transgenic lines and two mutant strains with which to investigate these questions, and are utilising genetics, immunohistochemistry, confocal microscopy, scanning electron microscopy, molecular biology, bioinformatics and other approaches in our research. Projects are available in either area, and can be adjusted to suit particular interests.

CAPTION...

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References:

Robertson, H., G.R. Hime, and D.D.L. Bowtell (2000) "A Drosophila analogue of v-Cbl is a dominant negative oncoprotein in vivo." Oncogene 19, 3299-3308

Potter, C. J . et al. (2000). Drosophila in cancer research. An expanding role. Trends in Genetics 16, 33-9.