Nicolas La Thangue - Overview

During the cell cycle the transcription of a large group of genes is integrated with the transition through G1 into S phase. In mammalian cells the E2F transcription factor is believed to govern this process by co-ordinating early cell cycle progression through its cyclical interactions with key regulators of the cell cycle, such as the retinoblastoma tumour suppressor protein (pRb) and cyclin-dependent kinases (cdks). Most importantly, the pRb/E2F pathway is frequently deregulated in human tumour cells, either through the direct mutation in the Rb gene, or the aberrant control of cdk activity. It is known that E2F is a heterodimeric transcription factor composed of an E2F and DP family member, the transcriptional activity of which is governed by co-activator proteins, such as the p300/CBP family. As such, transcriptional control of E2F is regulated through a pathway that links the machinery of the cell cycle with the transcriptional apparatus. An objective of this laboratory is to perform a detailed molecular and functional characterisation of the E2F pathway. The p53 gene is frequently mutated in human cancer. The p53 protein exerts tumour suppression in part by modulating the pRb/E2F pathway. Some p53 target genes, such as p21, block cdk activity and thereby maintain pRb activity. Whilst transcriptional regulation by p53 is a key component of the p53 response, relatively little information is available on the mechanisms involved in facilitating transcriptional activation by p53. Given the pivotal role of the pRb/E2F and p53 pathways in growth control, the information gained from our work will be of significant importance for understanding the normal cell cycle and provide novel insights into the regulation of cancer cell growth. As such the study is likely to identify new therapeutic approaches for the treatment of cancer.