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

动物细胞的生长和分裂需要基因表达以协调的方式打开和关闭。细胞分裂的过程称为细胞周期，在此期间染色体首先被复制，然后一个细胞分裂为两个。一个主要的控制点发生在第一个G1期，在此期间细胞致力于复制其染色体并分裂或退出细胞周期。在正常细胞中，细胞周期是一个严格调控的过程，但在人类疾病中经常出错。所涉及的关键蛋白质，视网膜母细胞瘤肿瘤抑制蛋白pRb及其关键靶点E2 F，控制着通过G1的进展和细胞分裂的承诺。这项研究解决了负责正常细胞周期调节的机制，重点关注影响E2 F调节特性的酶控制的新水平，重点关注E2 F-1亚基，它表现出一些非常有趣和不寻常的生物学特性;例如，它能够促进细胞生长和存活，反过来刺激细胞死亡。关于控制E2 F-1活性的这些对比生物学结果的分子机制还没有真正了解，这是本申请的重点。具体而言，该计划将剖析E2 F-1在细胞中发挥其生物学作用的分子机制和细胞过程。我们将专注于赋予E2 F相反的生物学特性的机制，并探索负责的细胞途径和分子过程。我们的实验方法使用先进的方法来解决E2 F如何在基因组和蛋白质组水平上发挥作用的重要问题，我们与一组专家合作来实现这些目标。我们的研究的总体目标是详细了解E2 F在正常细胞中的作用，以及负责控制其独特生物学作用的机制。这项研究很可能阐明与人类疾病相关的新机制和信息。

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.