RED CELL CYTOSKELETAL PROTEIN 41 DURING 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。子项目及 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 研究中心，而研究中心不一定是研究者的研究机构。 多功能结构蛋白，作为接头或衔接子，是细胞重塑过程所必需的。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有助于细胞分裂和分化。蛋白4.1R最初在成熟红细胞中被鉴定为对红细胞骨架组织和机械稳定性至关重要的动态连接复合物中的多功能结构蛋白。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。我们报道了4.1是体外正常核组装以及正常有丝分裂纺锤体和中心体形成所必需的。在完整的哺乳动物细胞中，我们发现，4.1R的RNA干扰耗竭损害中心体结构，有丝分裂和胞质分裂的保真度，并改变细胞周期进程。根据我们的观察，我们假设4.1相互作用连接中心体和细胞核的结构成分，以提供细胞分裂和分化过程中快速组装/拆卸所需的动态特性。我们以前确定血影蛋白/肌动蛋白结合结构域和4.1R的C-末端结构域直接在这些亚细胞结构的组装中起作用。我们目前的目标是通过识别4.1R结合伴侣并分析4.1如何调节其功能，来详细了解4.1R相互作用和机制，这些相互作用和机制有助于细胞分裂和分化中的组装/拆卸过程中的细胞重塑。我们预计，识别蛋白4.1的功能相互作用将进一步增加我们对细胞分裂和分化过程中细胞核、中心体和有丝分裂纺锤体的组装和动力学基本原理的理解。这反过来可能表明4.1R基因缺陷的先前未被认识的病理后果的起源。此外，我们的研究将有助于对涉及缺陷或缺乏细胞骨架蛋白的分子疾病位点的广泛观点。

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.