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两种主要细胞途径：核糖体生物发生和细胞周期之间通信的分子基础。核糖体是细胞蛋白质生产机器，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，这是唯一合乎逻辑的。近年来，这两种途径之间的一些联系已经被确定，然而，它们之间的任何通信是如何实现的机制尚不清楚。在我过去的工作中，我已经确定了两种蛋白质，Rrp14p和Nop15p，它们似乎在核糖体合成和细胞周期的非常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，而且也是细胞纺锤体的正确位置所必需的，纺锤体可以物理地分离重复的染色体，以及母细胞和子细胞分离的正确时间。这些蛋白质如何与细胞分裂机制相互作用以实现这种控制仍然未知。我们将以出芽酵母酿酒酵母为模型系统，表征和研究与Rrp14p和Nop15p物理相互作用的细胞周期机械成分及其功能的调控机制。这将首次深入了解两种主要细胞通路如何相互沟通以协调和调节彼此。此外，该项目将为进一步研究核糖体生物发生和细胞分裂之间的分子机制奠定基础，这一主题在高等真核生物中变得越来越重要，其中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.