Melanoma is the most deadly form of skin cancer, and incidence continues to rise rapidly each year. In the UK, 2000 people die prematurely each year from melanoma, and once melanoma has spread there are no current treatments that successfully can be used to treat the disease. One of the ways in which melanoma can develop is from moles and we have developed a mole-to-melanoma model of cancer progression based on the most frequently mutated human gene in melanoma using the vertebrate animal called zebrafish. The way cancer develops and looks in zebrafish is highly similar to human cancers, and the genetic pathways that are altered in zebrafish cancers are the same as in people. The advantage for us with this system is that we can quickly and easily explore the function of many genes in melanoma development, as well as environmental factors that may contribute to disease. We can also test thousands of new and known chemicals in the zebrafish system that may be relevant to melanoma growth and movement in the body. Finally, the same genes that promote melanoma can also cause a syndrome called cardio-facial-cutaneous (CFC) syndrome, and we are developing new ways to look how the knowledge we gain from our melanoma studies may in fact be directly relevant to how we approach treatment for CFC.

We have identified three genes which, when mutated, can cause developmental malformations of the eye. These cause absence of the iris (or aniridia), and no eyes or small eyes. All three genes produce DNA-binding proteins which regulate the expression of other genes during development. We are exploring the complex regulation of these genes in cultured cells and in mouse and zebrafish models. Using existing information on what DNA sequences bind the aniridia gene PAX6, we can predict other targets for this gene and check their validity in the fish model. These targets are almost certainly conserved in mammals as well. Genes identified in this way are part of an interacting network that may include new genes causing other eye diseases. We are also exploring why no eyes and small eyes may not always manifest, even when the causative mutations are there. One protein that we have shown to play a role in this variability is called a chaperone because it helps newly formed and accidentally unfolded proteins to fold properly. The chaperone protein has a network of helpers that tells us how environmental factors influence gene function.

Wilms tumour is a kidney cancer that is quite common in children during the first 5 years of life. It is clearly a remarkable example of cancer arising through the normal processes of development going wrong. In order to understand how the tumour develops with a view to better treatments, we have to understand the processes of normal kidney development and how these go awry on the route to tumorigenesis. We are studying a Wilms tumour predisposition gene, WT1, mutations in which result in Wilms tumour but may also lead to other life-threatening kidney diseases and abnormalities of the sexual organs. We have shown that this gene is vital for normal kidney, testis and ovary development and one of our major goals is to understand how WT1 controls differentiation of these tissues and why disease develops when the gene is mutated. We have shown that WT1 is necessary for cells to divide and to prevent differentiation in certain tissues such as blood vessels of the heart. We propose to dissect WT1s role in these processes and to test the idea that it may play a major role in stem cell maintenance, tissue repair and in adult cancer. We have also shown WT1 is a remarkable example of a single gene encoding multiple proteins that may differentially regulate gene expression both in the nucleus and in the cytoplasm. One of our major goals is to understand these functions and how they control normal development and disease. We are taking a multidisciplinary approach to our work and are trying to set-up novel systems in culture to test the function of WT1 and associated genes.

DNA carries the genetic information of a cell and consists of thousands of genes that encode all the information required to make proteins. Genes (DNA) are copied into a molecule called RNA (pre-mRNA) in a process known as transcription. This pre-mRNA is then processed so that non-coding parts are removed and is then transported out of the nucleus to be ultimately translated into proteins in the cytoplasm. Our laboratory is interested in different aspects of how the pre-mRNA is accurately processed into mature mRNA, which then undergoes translation as part of the protein synthesis to produce proteins. Defects in RNA processing are linked to human disease. Our research program is at the basic end of the spectrum and we expect to contribute to the general knowledge in the areas of RNA processing and nuclear structure that could be applicable to human genetics.

Proteins control most of the important reactions carried out within cells. It is widely recognised that the timely removal of proteins by protein destruction is easily as important as making proteins at the correct time. In humans when this process goes wrong the results are catastrophic for the individual causing a wide range of debilitating diseases such as cancer, Alzheimers and Parkinsons disease. Proteins are targeted for destruction by being marked by the addition of a ubiquitin chain. The chain acts as flag, which is recognised by the cell and the protein rapidly turned over by the 26S proteasome, which acts as a protein shredder. We study how the ubiquitin flag is recognised by the cell. Previously, we have identified a number of flag recognition proteins. We propose to carry out a number of experiments to investigate how these flag recognition proteins can interact with the flag adding machinery of the cell and then present the marked proteins for degradation by the 26S proteasome.||Recently, another protein flag called Nedd8 has been shown to be added to many different proteins. The function of Nedd8 addition to proteins is at present unclear but it is known that it does not target them for destruction. But as a substantial number of proteins seem to be modified in this way it seems that modification by this protein will have important implications for intracellular regulation. We propose to identify the different proteins modified by this protein flag and investigate how modification alters the properties of the protein.