Mechanisms of Nuclear Positioning and Microtubule Organization

描述（由申请人提供）：在细胞周期和发育过程中，微管组织中心（MTOCs）的调控有助于微管细胞骨架的重组。分裂酵母裂糖酵母在细胞周期中使用三种类型的MTOCs来构建不同的微管结构。在间期，微管束由核膜上的多个间期微管组织中心（iMTOCs）组织。iMTOCs是核定位所必需的，可能含有参与微管成核、捆绑和附着于核膜的蛋白质。imtoc的建立发生在细胞质分裂过程中，与位于细胞分裂位点的赤道MTOC （eMTOC）的分解同时发生。在这里，我们将确定协调eMTOC分解和imtoc形成的机制。我们的具体目标是：1)确定j结构域蛋白rsp1p和MTOC蛋白coi1p在Emtoc分解调控中的作用。2)确定含MTOC分量的运动粒子（卫星）的功能。我们将测试一个模型，即卫星将MTOC成分从拆解的eMTOC运送到核膜，在那里它们有助于iMTOC的形成。3)鉴定将iMTOCs和间期MT束附着在外核膜上进行核定位的核膜蛋白。这项工作将为许多细胞类型（如上皮细胞和肌肉细胞）的微管调节提供见解。由于中心体缺陷在癌症中普遍存在，因此MTOC调控是目前癌症研究的一个重要领域。

DESCRIPTION (provided by applicant): Regulation of microtubule organizing centers (MTOCs) contributes to the reorganization of the microtubule cytoskeleton during the cell cycle and in development. Fission yeast Schizosaccharomyces pombe cells use three types of MTOCs for building different microtubule structures through the cell cycle. During interphase, microtubule bundles are organized by multiple interphase microtubule organizing centers (iMTOCs) on the nuclear envelope. iMTOCs are required for nuclear positioning and may contain proteins involved in microtubule nucleation, bundling and attachment to the nuclear envelope. Establishment of iMTOCs occurs during cytokinesis, concurrent with the disassembly of the equatorial MTOC (eMTOC) located at the cell division site. Here, we will determine mechanisms that orchestrate the breakdown of the eMTOC and the formation of iMTOCs. Our specific aims are: 1) to determine the roles of a J-domain protein rsp1p and an MTOC protein coi1p in regulation of Emtoc disassembly. 2) To determine the function of motile particles (satellites) containing MTOC components. We will test a model that satellites transport MTOC components from the disassemblying eMTOC to the nuclear envelope, where they contribute to iMTOC formation. 3) To identify nuclear envelope proteins that attaches iMTOCs and interphase MT bundles to the outer nuclear envelope for nuclear positioning. This work will provide insights into the regulation of microtubules of many cell types such as epithelial and muscle cells. As centrosomal defects are prevalent in cancer, MTOC regulation is now an important area in cancer research.