Interactions between ribosome biogenesis and regulatory networks of cell division in eukaryotic cells

我们研究计划的长期目标是了解核糖体生物发生和细胞周期这两条主要细胞途径之间沟通的分子基础。核糖体是细胞蛋白质生产的机械，因此蛋白质生产对细胞生长和细胞分裂能力至关重要。因此，核糖体的合成与细胞分裂的调节密切相关，这是合乎逻辑的。近年来，人们已经发现了这两条通路之间的几种联系，然而，目前还不清楚它们之间的沟通机制是如何实现的。在我过去的工作中，我已经确定了Rrp14p和Nop15p这两种蛋白质，它们似乎在核糖体合成和细胞周期的特定阶段之间形成了重要的控制联系。它们在细胞内的存在不仅是正确的核糖体组装所必需的，也是正确的细胞纺锤体位置(物理上分离重复的染色体)和正确的母细胞和子细胞分离时间所必需的。这些蛋白质是如何与细胞分裂机制相互作用来实现这种控制的，目前尚不清楚。以发芽酵母S.cerevisiae为模型系统，我们将表征和研究与Rrp14p和Nop15p物理相互作用的细胞周期机械组件，以及它们潜在的功能调控机制。这将让我们第一次洞察两条主要的细胞通路是如何相互通信的，以便相互协调和调节。此外，该项目将为进一步研究核糖体生物发生和细胞分裂的分子机制奠定基础，这一主题在高等真核生物中正变得越来越重要，核糖体生物发生因子如NIFK(HNOP15)的缺陷被证明会导致恶性细胞增殖和疾病发展。

The long-term objective of our research program is to understand the molecular basis for the communication between two major cellular pathways: ribosome biogenesis and the cell cycle. Ribosomes are the cellular protein production machinery and as such very important as protein production is imperative for cell growth and a cell's ability to divide. Thus it is only logical that the synthesis of ribosomes is tightly linked to the regulation of cell division. Several connections between these two pathways have been identified in recent years, however, it is still unclear how mechanistically any communication is achieved between them. In my past work I have identified to proteins, Rrp14p and Nop15p, that appear to form an important control link between ribosome synthesis and very specific stages of the cell cycle. Their presence within cells is required not only for correct ribosome assembly, but also for correct position of the cell spindle, which physically segregates duplicated chromosomes, and correct timing of mother and daughter cell separation, respectively. How these proteins interact with the cell division machinery to achieve such control is still unknown. Using the budding yeast S.cerevisiae as our model system, we will characterize and study cell cycle machinery components that physically interact with Rrp14p and Nop15p, as well as regulatory mechanisms underlying their functions. This will provide a first insight into how two major cellular pathways communicate with each other in order to coordinate and regulate one another. Moreover, the project will set the stage for further investigations into the molecular mechanisms linking ribosome biogenesis and cell division, a topic that is becoming increasingly important in higher eukaryotes, where defects in ribosome biogenesis factors such as NIFK (hNOP15) were shown to result in malignant cell proliferation and disease development.