The E2F pathway: new levels of control and regulation

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, block 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.

E2F transcription factors are widely viewed as essential regulators of cell cycle progression through their ability to co-ordinate and integrate cell cycle events with the transcription machinery. E2F activity has been connected with a variety of cell fates, including differentiation, apoptosis, senescence and autophagy, and is attributed with a major role in driving tumourigenesis. Since the original definition of E2F DNA binding complexes in mammalian cells, it has become apparent that E2F is a family of transcription factors with diverse physiological roles that has been highly conserved throughout evolution. It remains a major challenge to decipher the biology of individual E2F family members, and understand the physiological cues that drive the diverse outcomes that have been assigned to E2F activity. Knowledge about the regulatory events that influence E2F activity is therefore of considerable importance in understanding the complexity of cell cycle control and abnormalities that contribute to cancer.