MOLECULAR MECHANISMS REQUIRED FOR COORDINATION OF CELL GROWTH AND CELL DIVISION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 真核细胞在大小和形态上表现出非凡的多样性。由于每种细胞类型的特征在于独特的大小和形状，细胞生长的控制是细胞形式，功能和身份不可或缺的。细胞生长很可能是由高度复杂的机制控制的，因为单细胞生物体可以在广泛变化的生长条件下保持相同的大小和形状，而多细胞生物体由大小和形状差异很大的细胞组成。在芽殖酵母和裂殖酵母中的遗传实验已经证明细胞周期蛋白依赖性激酶在控制细胞生长中起关键作用;然而，它们这样做的分子机制知之甚少。 我们的研究重点是了解细胞周期蛋白依赖性激酶如何协调芽殖酵母有丝分裂过程中的细胞生长和细胞分裂。有丝分裂细胞周期蛋白依赖性激酶复合物的失活导致在G2/M停滞期间的连续细胞生长，引起高度伸长的细胞的形成。伸长的细胞比野生型细胞长得大得多，表明控制细胞大小和细胞生长的机制严重失败。我们已经发现，一个复杂的信号网络功能在G2/M期控制细胞生长。生物化学和遗传学数据表明，该信号网络受有丝分裂CDK活性调节，并在调节Wee 1激酶的芽殖酵母同系物中发挥重要作用，Wee 1激酶已被证明在协调裂殖酵母中的细胞生长和有丝分裂中发挥核心作用。我们最近的工作表明，Swe 1与有丝分裂Cdk复合物和参与细胞生长的蛋白质直接相关，为协调细胞生长与细胞周期的长期神秘分子机制提供了第一条线索。 我们未来工作的重点将是利用生物化学和遗传学方法来了解协调细胞生长和细胞分裂的分子信号机制。 我们工作的另一个主要重点是了解控制细胞周期G1期的机制。G1是细胞评估外部条件和细胞大小的关键时期，然后决定是否进行新一轮细胞分裂。 G1期的细胞只有在达到临界大小并以生长因子或营养物质的形式接收到适当的外部信号时，才开始新一轮的细胞分裂。虽然已经确定了G1期事件的一些关键调节因子，但我们仍然不了解将细胞大小和外部信号与进入细胞周期整合的分子机制。我们已经发现了一个高度保守的蛋白质，这是进入G1期所需的芽殖酵母。此外，在上述有丝分裂信号网络中起作用的许多蛋白质似乎也参与控制通过G1。我们目前正在使用相同的生化和遗传方法，我们正在使用有丝分裂信号网络的特点G1控制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Eukaryotic cells show extraordinary diversity in size and morphology. Since each cell type is characterized by a unique size and shape, the control of cell growth is integral to cellular form, function, and identity. It is likely that cell growth is controlled by highly intricate mechanisms, since single-celled organisms can maintain the same size and shape over widely varying growth conditions, and multicellular organisms are composed of cells of widely differing size and shape. Genetic experiments in both budding yeast and fission yeast have demonstrated that cyclin-dependent kinases play a critical role in controlling cell growth; however, the molecular mechanisms by which they do so are poorly understood. The focus of our research is to understand how cyclin-dependent kinases coordinate cell growth and cell division during mitosis in budding yeast. Inactivation of mitotic cyclin-dependent kinase complexes results in continuous cell growth during a G2/M arrest, causing the formation of highly elongated cells. The elongated cells grow significantly larger than wild type cells, indicating a severe failure in the mechanisms that control cell size and cell growth. We have found that an intricate signaling network functions during G2/M to control cell growth. Biochemical and genetic data argue that this signaling network is regulated by mitotic CDK activity and plays an important role in regulating the budding yeast homolog of the Wee1 kinase, which has been shown to play a central role in coordinating cell growth and mitosis in fission yeast. Our most recent work suggests that Swe1 associates directly with mitotic Cdk complexes and proteins involved in cell growth, providing the first clues to the long mysterious molecular mechanisms that coordinate cell growth with the cell cycle. A focus of our future work will be to use biochemical and genetic approaches to understand the molecular signaling mechanisms that coordinate cell growth and cell division. Another major focus of our work is to understand the mechanisms that control passage through the G1 phase of the cell cycle. G1 is a crucial period where cells assess external conditions and cell size, and then make a decision regarding whether to commit to a new round of cell division. Cells in G1 initiate a new round of cell division only when they have reached a critical size and have received the appropriate external signals in the form of growth factors or nutrients. Although a number of key regulators of G1 events have been identified, we still do not understand the molecular mechanisms that integrate cell size and external signals with entry into the cell cycle. We have discovered a highly conserved protein that is required for entry into G1 in budding yeast. In addition, a number of the proteins that function in the mitotic signaling network described above also appear to be involved in controlling passage through G1. We are currently characterizing G1 control using the same biochemical and genetic approaches that we are using to characterize mitotic signaling networks.