ANALYSIS OF CELL TRANSFORMATION BY ONCOGENIC RAS USING NOVEL FUNCTIONAL GENOMICS APPROACHES

Transformation of cells by Ras and other oncogenes leads to profound changes in their gene expression programmes. Two decades of intense study of signaling pathways has led to a good understanding of many of the early signaling events induced on stimulation of oncoproteins such as Ras. In addition, recent advances in microarray technology have provided much information about the changes in transcription that accompany transformation. However, the key medium term events required to set up the transcriptional programme underlying malignant transformation are much less well defined, but may include a number of good therapeutic targets. We have set out to study a number of aspects of cellular transformation using large-scale RNA interference libraries, including the 8000 gene NKI library (Berns et al., 2004). This library is in a retroviral vector that can be used either in selective screens in a pooled format, or in phenotypic screens in a high throughput format. To find novel signalling proteins regulated by Ras, we have undertaken a selective RNA interference screen for inhibitors of Ras induce