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

动物细胞的生长和分裂需要以协调的方式开启和关闭基因表达。细胞分裂的过程被称为细胞周期，在这个过程中，染色体首先被复制，然后一个细胞分裂成两个。一个主要的控制点发生在第一个G1期，在这个阶段，细胞承诺复制它们的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变得不正常。参与其中的关键蛋白是视网膜母细胞瘤肿瘤抑制蛋白PRB及其关键靶点E2F，它们通过G1和细胞分裂的承诺来控制进展。这项研究探讨了正常细胞周期调控的机制，重点是影响E2F调节特性的酶调控的新水平，重点是E2F-1亚单位，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，并反过来刺激细胞死亡。关于控制E2F-1活性的这些不同生物学结果的分子机制尚不真正清楚，这是本应用的重点。具体地说，该计划将剖析E2F-1在细胞中发挥其生物学效应的分子机制和细胞过程。我们将集中于赋予E2F相反生物学特性的机制，并探索相关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E2F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者合作来实现这些目标。我们的研究的首要目标是详细了解E2F在正常细胞中的作用，以及负责控制其不同生物学作用的机制。这项研究很有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.