RED CELL CYTOSKELETAL PROTEIN 41 DURING CELL DIVISION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多功能结构蛋白作为连接物或接头，对细胞重塑过程是必不可少的。我们的研究集中在细胞骨架蛋白4.1R的分子相互作用如何促进细胞分裂和分化。蛋白4.1R最初在成熟的红细胞中被鉴定为一种多功能结构蛋白，存在于动态连接复合体中，对红细胞骨架组织和机械稳定性至关重要。然而，随后发现蛋白4.1R在非红系和红系有核细胞中普遍表达，并在中心体、有丝分裂纺锤体和细胞核中检测到。我们报道，4.1是正确的核组装以及在体外形成适当的有丝分裂纺锤体和中心体所必需的。在完整的哺乳动物细胞中，我们发现RNA干扰导致的4.1R缺失损害了中心体结构、有丝分裂和胞质分裂的保真度，并改变了细胞周期进程。根据我们的观察，我们假设4.1相互作用将中心体和核的结构成分联系在一起，提供细胞分裂和分化过程中快速组装/拆卸所需的动态性质。我们先前发现，4.1R的光谱蛋白/肌动蛋白结合域和C-末端结构域直接参与这些亚细胞结构的组装。我们目前的目标是通过识别4.1R结合伙伴并分析4.1如何调节它们的功能，来详细了解4.1R相互作用和在细胞分裂和分化的组装/拆卸过程中促进细胞重塑的机制。我们预计，识别蛋白质4.1的功能相互作用将进一步加深我们对细胞核、中心体和有丝分裂纺锤体在细胞分裂和分化过程中组装和动力学的基本原理的理解。这反过来可能表明4.1R基因缺陷以前未知的病理后果的起源。此外，我们的研究将为涉及细胞骨架蛋白缺陷或缺陷的分子疾病基因座提供一个广阔的视角。

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. Multifunctional structural proteins, serving as linkers or adaptors, are essential for cellular remodeling processes. Our studies focus on how molecular interactions of the cytoskeletal protein 4.1R contribute to cell division and to differentiation. Protein 4.1R was initially identified in mature red cells as a multifunctional structural protein in dynamic junctional complexes crucial for red cell skeletal organization and mechanical stability. However, subsequently protein 4.1R was found to be ubiquitously expressed in non-erythroid and erythroid nucleated cells and detected at centrosomes, mitotic spindles, and in nuclei. We reported that 4.1 is required for proper nuclear assembly as well as proper mitotic spindle and centrosome formation in vitro. In intact mammalian cells, we showed that 4.1R depletion by RNA interference compromises centrosomal structure, the fidelity of mitosis and cytokinesis, and alters cell cycle progression. On the basis of our observations, we hypothesize that 4.1 interactions link structural components of centrosomes and nuclei to provide dynamic properties needed for rapid assembly/disassembly during cell division and during differentiation. We previously identified that the spectrin/actin binding domain and the C-terminal domain of 4.1R directly function in assembly of these subcellular structures. Our current goal is to obtain a detailed understanding of 4.1R interactions and mechanisms that contribute to cellular remodeling during assembly/disassembly in cell division and differentiation by identifying 4.1R binding partners and analyzing how 4.1 modulates their functions. We anticipate that identifying functional interactions of protein 4.1 will further increase our understanding of fundamental principles of assembly and dynamics of nuclei, centrosomes and mitotic spindles during cell division and differentiation. This in turn may indicate the genesis of previously unrecognized pathological consequences of 4.1R gene defects. Furthermore, our investigations will contribute a broad perspective on molecular disease loci involving defective or deficient cytoskeletal proteins.