Myb Oncogene
The Role of c-Myb in T-cell Development
The Myb transcription activator is an important regulator of thymopoiesis, the process whereby immature progenitors enter the thymus, become specialized and expand and differentiate to generate a functional repertoire of mature T cells. We are interested in finding out how Myb mediates its downstream effects at two specific points during T-cell development: during the process of positive selection, whereby mature thymocytes are generated, and during mature T-cell activation in response to antigen. We are studying this problem by biochemical characterisation of the phenotypes of cells in which Myb protein is no longer functional, or in which it is overexpressed. We have shown that changing the level of Myb protein activity causes a change in positive selection, suggesting that Myb plays a role in lineage choice. We are currently investigating how Myb interacts with other transcription factors and signalling pathways previously shown to regulate positive selection and the differentiation of mature T cells following antigenic challenge. In an associated project, we have identified other transcription factors with potential roles in lineage choice, and are investigating how they work and how they might impinge upon Myb function during this process.
Target Genes of the Myb Oncoprotein
The list of known Myb target genes is short, and those genes described do not adequately account for the biological effects of Myb protein. We have completed a screen for Myb targets and have identified and validated about 40 genes hitherto not known to lie downstream of Myb proteins. We are now focussing on a subset of these target genes which might contribute to the oncogenic and developmental effects of Myb, specifically the histone variant H2A.Z, and also a set of genes implicated in regulating migration and invasion of tumour cells. We intend to find out exactly how, where and when Myb regulates these genes, and whether and how they work as Myb effectors in normal and neoplastic development.
Function of the Myb Oncoprotein in Oesophageal Adenocarcinoma
Oesophageal adenocarcinoma is the eighth most common cancer in the UK, and the incidence of its pre-cancerous precursor Barrett’s oesophagus is rising alarmingly. The MYB proto-oncogene is frequently over-expressed and remains up-regulated in progression from Barrett’s to adenocarcinoma, and we are using it as a molecular probe to determine how the normal oesophageal cells are dysregulated to cause a cancer. MYB has been shown to lie downstream of several major signal transduction pathways and its over-expression is likely to result from the aberrant activation of one or more of these pathways. Identification of the factors controlling MYB dysregulation will allow an understanding of the molecular events leading to adenocarcinoma. In addition to this work, we are also identifying and assaying MYB target genes in oesophageal adenocarcinoma cells, with a view to developing potential novel targets for therapeutic intervention in this unpleasant disease.
In the Section of Cell and Molecular Biology (including the Cancer Research UK Centre for Cell and Molecular Biology)
