Regulation of gene expression during cell transformation and tumorigenesis
Previous and current research:
We are interested in how cancer cells evade normal mechanisms for the control of proliferation and survival. Many oncogenes deregulate the pathways that transmit signals from the cell surface to the transcription machinery in the cell nucleus. Components of the Ras signalling pathway are frequently activated in human tumours and render cells insensitive to a number of growth inhibitory stimuli. Two of the major downstream effectors of oncogenic Ras are the serine/threonine kinases Raf and PKB/Akt. Using gene expression analysis by DNA microarray, we have analysed the transcriptional programme induced by activated Raf1 and identified a major autocrine component. We have also shown that PKB/Akt induces transcription of a number of key enzymes involved in fatty acid and cholesterol biosynthesis through activation of sterol-responsive-element-binding-proteins (SREBPs). NMR analysis of cellular lipids revealed that activation of PKB/c-Akt induces an increase in fatty acids and phosphoglycerides. Activation of SREBP by Akt may be involved in regulation of de novo synthesis of cellular membranes and thus required for cell growth.
Future projects:
Regulation of metabolic and anabolic pathways is crucial for cell proliferation and tissue maintenance and a number of metabolic enzymes have been identified as oncogenes or tumour suppressors. We are currently investigating the mechanism of activation of SREBP by Akt. We are also extending our analysis of the involvement of SREBP activation in Akt induced cell growth.
Analysis of gene expression can reveal insight into the activation state of cellular signalling pathways. We are using human airway epithelial cells with defined genetic lesions as an in vitro model for Ras induced transformation and tumorigenesis. We are planning to employ gene expression analysis in order to identify pathway specific expression signatures. This system can also be used to identify potential tumour suppressor genes that may play a role in the development of lung cancer.
