The E2F pathway of growth control

Cancer results from abnormal cell growth and division, and is frequently described as a disease of the cell cycle. The cell cycle refers to the process through which one cell grows and divides which, in normal healthy cells, is a tightly regulated process. The cell cycle is divided into four phases, where a major point of control exists as cells progress from the initial G1 phase into S phase, which is when cells begin to synthesise and copy their DNA in preparation for cell division. In mammalian cells, E2F is a control protein of central importance because it governs whether cells do or do not enter S phase. The activity of E2F is regulated by a number of key proteins that act as a ?braking? system, and includes the retinoblastoma tumour suppressor protein (pRb) which, by forming a protein complex with E2F, blocks E2F activity. Most importantly, in human tumour cells pRb is usually inactive, which means that the normally tightly regulated E2F activity is unleashed, providing a permanent signal that drives cells into unrestrained growth and division. The programme of study described here wants to dissect the role and regulation of different types of E2F activity, and assess the contribution to normal and tumour cell growth. Because of the abnormal control of E2F in cancer, this study is likely to identify new therapeutic opportunities for preventing the growth of tumour cells.

The E2F family of heterodimeric transcription factors plays a central role in regulating cellular proliferation by controlling the expression of genes required for cell cycle progression. E2F is regulated in a cell cycle-dependent manner, principally through its temporally regulated association with pocket protein family members, such as the retinoblastoma tumour suppressor protein (pRb), the gene for which is frequently mutated or functionally inactivated in human tumour cells leading to the release of aberrant levels of E2F. Pocket proteins are regulated through phosphorylation by cyclin-dependent kinases, which modulate the interaction between pRb and E2F. In turn E2F transcriptional activity is governed by the physical interaction of co-activator protein complexes with the transcriptional activation domain. As such, E2F is controlled by a pathway that links the machinery of the cell cycle with the transcription apparatus. More recently, the E2F pathway has been shown to be under DNA damage control, which leads to apoptosis. The focus of this programme is to address an interconnected series of questions towards gaining a detailed understanding of the E2F pathway of control. The proposals capitalize on novel insights generated in previous studies on the role of E2F in the DNA damage response together with recent findings on new E2F subunits that exhibit some unusual properties. Given the fundamental role that the pRb/E2F pathway plays in regulating growth, together with its frequent deregulation in human tumour cells, it is likely that the information gained from this study will not only impact on our knowledge of normal growth control, but also provide new insights into cancer cell growth.