Regulation of Differentiation in Caulobacter

描述（由申请人提供）：本提案的目的是定义控制细菌细胞周期的调节机制，并了解这些机制如何在集成系统中发挥作用。我们已经表明，新月柄杆菌细胞周期的控制包括离散的转录模式，受控的蛋白水解事件，其在细胞周期的限定时间清除细胞中的关键调节蛋白，以及协调细胞周期调节剂活性的极性磷酸信号传导蛋白的动态定位。一个由三个全局调节因子（CtrA，GcrA，DnaA）控制的转录网络，在时间和空间上异相振荡，已被证明可以调节大约200个基因的时间表达。这种转录网络影响细胞的亚细胞组织及其在细胞周期中的渐进变化，并受其影响。细胞分裂前的细胞区室化是子细胞中特异性蛋白水解事件差异激活的关键信号。负责CtrA全局调节剂的及时降解的ClpXP蛋白酶必须与其CtrA底物一起定位于细胞极以实现该功能。此外，ClpXP定位的时间由来自瞬时定位的CckA组氨酸激酶的信号传导控制，所述CckA组氨酸激酶也在细胞周期中的正确时间介导CtrA的活化，从而产生稳健的转录网络。我们将专注于确定负责蛋白质定位和动态调节的蛋白水解机制，在细胞周期进程中发挥根本作用的因素，并确定有助于和整合细胞周期调控网络的因素。此外，由于自由生物体必须随时适应不断变化的环境，因此了解这种调节回路不仅在最佳条件下如何工作，而且在细胞受到挑战时如何重新编程，以及当条件再次有利时，它如何重新开始，这一点至关重要。我们将深入探索个体调节机制，同时确定它们如何在一个在时间和空间上运行以执行活细胞功能的集成系统中发挥作用。

DESCRIPTION (provided by applicant): The goal of this proposal is to define the regulatory mechanisms that control the bacterial cell cycle and to understand how these mechanisms function within an integrated system. We have shown that the control of the Caulobacter crescentus cell cycle incorporates discrete transcription patterns, controlled proteolytic events that clear the cell of critical regulatory proteins at defined times in the cell cycle, and dynamic localization of polar phospho- signaling proteins that orchestrates the activity of cell cycle regulators. A transcriptional network governed by three global regulators (CtrA, GcrA, DnaA) that oscillate out of phase temporally and spatially has been shown to regulate the temporal expression of approximately 200 genes. This transcriptional network influences and is influenced by the subcellular organization of the cell and its progressive changes during the cell cycle. Cellular compartmentalization preceding cell division is a critical signal for the differential activation of specific proteolytic events in the daughter cells. The CIpXP protease, responsible for the timely degradation of the CtrA global regulator, must be localized at the cell pole with its CtrA substrate for this function. Further, the timing of CIpXP localization is controlled by signaling from the transiently localized CckA histidine kinase that also mediates the activation of CtrA at the correct time in the cell cycle, thus creating a robust transcriptional network. We will focus on identifying the factors responsible for protein localization and the dynamic regulation of the proteolytic mechanisms that play a fundamental role in cell cycle progression, and identifying the factors that contribute to and integrate cell cycle regulatory networks. In addition, because free living organisms must readily adapt to a changing environment, it is critical to understand how this regulatory circuitry works not only under optimal conditions, but also how it is re-programmed when the cell is challenged; and how, when conditions are favorable again, it begins anew. We will explore individual regulatory mechanisms in depth while determining how they function in an integrated system that operates in time and space to carry out the functions of a living cell.