Fundamental biology of E2F transcription factors: investigating the role of arginine methylation

点击翻译按钮获取中文摘要

Growth and division of animal cells requires gene expression to be turned on and off in a coordinated fashion. The process of cell division is called the cell cycle, during which chromosomes are first copied and then one cell divides into two. A major point of control occurs during the first G1 phase, where cells commit to replicate their chromosomes and divide or alternatively exit the cell cycle. In normal cells, the cell cycle is a tightly regulated process, but frequently becomes awry in human disease. The key proteins involved, the retinoblastoma tumour suppressor protein pRb and its crucial target E2F, govern progress through G1, and the commitment of cells to divide. This research addresses the mechanisms which are responsible for normal cell cycle regulation focussing on new levels of enzymatic control which influence the regulatory properties of E2F, focussing on the E2F-1 subunit, which exhibits some profoundly interesting and unusual biological properties; for example, it is able to prompt cell growth and survival, and conversely stimulate cell death. Nothing is really known about the molecular mechanisms which control these contrasting biological outcomes of E2F-1 activity, which is the focus of this application. Specifically, the programme will dissect the molecular mechanisms and cellular processes through which E2F-1 exerts its biological effects in cells. We will concentrate on the mechanisms which endow E2F with its opposing biological properties, and probe the cellular pathways and molecular processes that are responsible. Our experimental approach uses advanced methodologies to address important questions on how E2F exerts its effects at the genome and proteome level, and we work with a group of expert collaborators to achieve these aims. Our research has the overarching aim of delivering a detailed understanding of the role of E2F in normal cells, and the mechanisms which are responsible for controlling its distinct biological roles. The study is very likely to illuminate new mechanisms and information that is relevant to human disease.