Red Cell Cytoskeletal Protein 4.1 During Cell Division

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。这项建议的长期目标是阐明结构蛋白，特别是细胞骨架蛋白4.1的分子相互作用如何促进细胞分裂。蛋白质4.1是一种多功能结构蛋白，它在红细胞中整合了对调节红细胞骨架组织和机械稳定性至关重要的成分。然而，现在已经证实，蛋白4.1在非红系有核细胞和红系细胞中都有表达，并在中心体、有丝分裂纺锤体和核等部位被检测到。尽管蛋白质4.1在成熟红细胞中的作用已经很清楚，但它在有核细胞中的作用(S)还不是很清楚。我们报道，4.1是微管组织和动力学所必需的，对于正常的有丝分裂纺锤体和中心体的形成是必要的。我们还发现，至少有两个4.1结构域直接参与了这些亚细胞细胞器的组装。我们的中心假设是，蛋白质4.1的相互作用连接或整合了中心体和纺锤体极内的结构成分，为细胞分裂过程中的组装/拆卸提供了必要的动态性质。为了更详细地了解相互作用和机制，我们提出了两个目标：(1)阐明4.1对有丝分裂纺锤体和中心体微管动力学和组织的调节机制；(2)确定4.1表达如何影响细胞分裂。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4.1基因缺陷以前未知的病理后果的起源。然而，我们的研究也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。

Multifunctional structural proteins, serving as linkers or adaptors, are essential for cellular remodeling processes. The long-term objective of this proposal is to elucidate how molecular interactions of structural proteins, particularly cytoskeletal protein 4.1, contribute to cell division. Protein 4.1 is a multifunctional structural protein that in red cells integrates components crucial for regulation of red cell skeletal organization and mechanical stability. However, it is now established that protein 4.1 is expressed in non-erythroid nucleated cells as well as in erythroid cells and is detected at sites such as centrosomes, mitotic spindles and nuclei. Although the role of protein 4.1 in mature red cells is well defined, its role(s) in nucleated cells are not well understood. We reported that 4.1 is required for microtubule organization and dynamics essential for proper mitotic spindle and centrosome formation. We also showed that at least two 4.1 domains directly function in assembly of these subcellular organelles. Our central hypothesis is that protein 4.1 interactions link or integrate structural components within centrosomes and spindle poles to provide dynamic properties necessary for assembly/disassembly during cell division. To obtain a detailed understanding of the interactions and mechanisms involved, two Aims are proposed: (1) elucidate mechanisms for 4.1 regulation of microtubule dynamics and organization in mitotic spindle poles and centrosomes, (2) determine how 4.1 expression affects cell division. We anticipate that identifying functional interactions of protein 4.1 will further increase our understanding of fundamental principles of assembly and dynamics of centrosomes and mitotic spindles during cell division and differentiation. This in turn may indicate the genesis of previously unrecognized pathological consequences of 4.1 gene defects. However, our investigations will also contribute a broad perspective on molecular disease loci involving defective or deficient cytoskeletal proteins.